Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders

ABSTRACT

The present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastereomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them. The present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the Formula (1), their analogs, tautomers, enantiomers, diasteromers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, appropriate N-oxide, pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.

This application is a divisional of U.S. patent application Ser. No.10/821,642, filed Apr. 9, 2004, now U.S. Pat. No. 7,223,789, which (i)claims the benefit of Indian Provisional Patent Application363/MUM/2003, filed Apr. 11, 2003 and U.S. Provisional PatentApplication 60/519,967, filed Nov. 13, 2003, and (ii) is acontinuation-in-part of International Application No. PCT/IB2004/000355,filed Feb. 11, 2004. All of these priority applications are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds, theiranalogs, their tautomers, their regioisomers, their stereoisomers, theirenantiomers, their diastereomers, their polymorphs, theirpharmaceutically acceptable salts, their appropriate N-oxides, theirpharmaceutically acceptable solvates and their pharmaceuticalcompositions containing them. The present invention more particularlyrelates to novel Phosphodiesterase type 4 (PDE4) inhibitors of theFormula (1), their analogs, their tautomers, their enantiomers, theirdiasteromers, their regioisomers, their stereoisomers, their polymorphs,their pharmaceutically acceptable salts, their appropriate N-oxide,their pharmaceutically acceptable solvates and the pharmaceuticalcompositions containing them.

The invention thus relates to compounds of the Formula (1)

wherein:

-   R¹, R² and R³ may be same or different and are independently    selected for each occurrence from the groups consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic group, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, formyl, acetyl, halogen, protecting groups,    —C(O)—R^(a), —C(O)O—R^(a), —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a),    —S(O)_(q)—NR^(a)R^(a), —NR^(a)R^(a), —OR^(a), —SR^(a) or when two R³    substitutents ortho to each other, may be joined to a form a    saturated or unsaturated cyclic 3-7 membered ring, which may    optionally include up to two heteroatoms which may be same or    different selected from O, NR^(a) or S;-   wherein R⁴ is —NR⁵R⁶; wherein R⁵ and R⁶ may be same or different and    are independently selected from the groups consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic ring, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, halogen, —C(O)—R^(a), —C(O)O—R^(a),    —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a), —S(O)_(q)—NR^(a)R^(a),    —C(═NR^(a))—R^(a), —C(═NR^(a))—NR^(a)R^(a), —C(═S)—NR^(a)R^(a),    —C(═S)—R^(a), —N═C(R^(a)R^(a)), —NR^(a)R^(a), —OR^(a), —SR^(a),    protecting groups or R⁵ and R⁶ to each other may be joined to a form    a saturated or unsaturated 3-7 membered cyclic ring, which may    optionally include up to two heteroatoms which may be same or    different selected from O, NR^(a) or S;-   Ar is selected from the group consisting of substituted or    unsubstituted aryl, substituted or unsubstituted arylalkyl,    substituted or unsubstituted heterocyclic ring and substituted or    unsubstituted heteroaryl ring;-   Preferably Ar is optionally substituted phenyl, optionally    substituted benzyl, optionally substituted pyrimidine, optionally    substituted pyridyl selected from 4-pyridyl, 3-pyridyl and 2-pyridyl    or optionally substituted pyridyl-N-oxide selected from    4-pyridyl-N-oxide, 3-pyridyl-N-oxide and 2-pyridyl-N-oxide in which    optional substituents (one or more) may be same or different and are    independently selected from the groups consisting of hydrogen,    hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or    unsubstituted alkylcarbonyl, substituted or unsubstituted    alkylcarbonyloxy, substituted or unsubstituted amino or mono or di    substituted or unsubstituted alkylamino-   X is selected from the group consisting of O, S(O)_(q) and NR^(a);-   Y is selected from the group consisting of —C(O)NR⁷, —NR⁷S(O)_(q),    —S(O)_(q)NR⁷ and —NR⁷C(O);-   R⁷ is selected from the group consisting of hydrogen, substituted or    unsubstituted alkyl, hydroxyl, —OR^(a), substituted or unsubstituted    aryl, and substituted or unsubstituted heterocyclic ring;-   wherein P is chosen from the group consisting of O and S;-   wherein m represents 0-3;-   wherein n represents 1-4;-   wherein q represents 0,1 or 2;-   with the proviso that R⁴ is not NH₂-   wherein R^(a) is selected from the group consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic ring, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, formyl, acetyl, halogen, protecting groups,    —C(O)—R^(a), —C(O)O—R^(a), —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a),    —S(O)_(q)—NR^(a)R^(a), —NR^(a)R^(a), —OR^(a) and —SR^(a);-   and their analogs, their tautomers, their regioisomers, their    stereoisomers, their enantiomers, their diastereomers, their    polymorphs, their pharmaceutically acceptable salts, their N-oxides,    their pharmaceutically acceptable solvates and their pharmaceutical    compositions containing them or a pharmaceutical acceptable salts    thereof.

The present invention also relates to a process for the preparation ofthe above said novel heterocyclic compounds of Formula 1 as definedabove.

The compounds of general Formula (1) more particularly, down regulate orinhibit the production of TNF-α as they are PDE4 inhibitors andtherefore are useful in the treatment of variety of allergic andinflammatory diseases including asthma, chronic bronchitis, atopicdermatitis, urticaria, allergic rhinitis, allergic conjunctivitis,vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoidarthritis, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and reperfusion injury of thebrain, chronic glomerulonephritis, endotoxic shock and adult respiratorydistress syndrome. The compounds of the present invention areparticularly useful for the treatment of asthma or chronic obstructivepulmonary disease (COPD).

BACKGROUND OF THE INVENTION

Airway inflammation characterizes a number of severe lung diseasesincluding asthma and chronic obstructive pulmonary disease (COPD).Events leading to airway obstruction include edema of airway walls,infiltration of inflammatory cells into the lung, production of variousinflammatory mediators and increased mucous production. The airways ofasthmatic patients are infiltrated by inflammatory leukocytes, of whichthe eosinophil is the most prominent component. The magnitude ofasthmatic reactions is correlated with the number of eosinophils presentin lungs.

The accumulation of eosinophils is found dramatically in the lungs ofasthmatic patients although there are very few in the lungs of a normalindividual. They are capable of lysing and activating cells anddestroying tissues. When activated, they synthesize and releaseinflammatory cytokines such as IL-1, IL-3, TNF-α and inflammatorymediators such as PAF, LTD4 and related oxygen species that can produceedema and broncho-constriction. Tumor necrosis factor (TNF-α) was alsoknown to be involved in the pathogenesis of a number of autoimmune andinflammatory diseases. Consequently, manipulation of the cytokinesignaling or biosynthetic pathways associated with these proteins mayprovide therapeutic benefit in those disease states. It has been welldemonstrated that TNF-α production in pro-inflammatory cells becomesattenuated by an elevation of intracellular cyclic adenosine3′,5′-monophosphate (cAMP). This second messenger is regulated by thephosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymesplay an integral role in cell signaling mechanisms by hydrolyzing cAMPand cGP to their inactive 5′ forms. Inhibition of PDE enzymes thusresults in an elevation of cAMP and/or cGP levels and altersintracellular responses to extra cellular signals by affecting theprocesses mediated by cyclic nucleotides. Since eosinophilis arebelieved to be a critical proinflammatory target for asthma,identification of the expression of the PDE 4 gene family in eosinophilsled to PDE 4 as potential therapeutic target for asthma [Rogers, D. F.,Giembycz, M. A., Trends Pharmacol. Sci., 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. Sci., 19, 415-423 (1998) herein incorporated byreference in their entirety].

The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classifiedinto ten families on the basis of their amino acid sequences and/or DNAsequence, substrate specificity and sensitivity to pharmacologicalagents [Soderling, S. H., Bayuga, S. J., and Beavo, J. A., Proc. Natl.Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J.,Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J.Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference intheir entirety]. Many cell types express more than one PDE anddistribution of isoenzymes between the cells varies markedly. Thereforedevelopment of highly isoenzyme selective PDE inhibitors provides aunique opportunity for selective manipulation of variouspathophysiological processes.

Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activitiesin cells which lead to inflammation in the lungs. PDE4, a cAMP-specificand Ca⁺²-independent enzyme, is a key isozyme in the hydrolysis of cAMPin mast cells, basophils, eosinophils, monocytes and lymphocytes. Theassociation between cAMP elevation in inflammatory cells with airwaysmooth muscle relaxation and inhibition of mediator release has led towidespread interest in the design of PDE4 inhibitors [Trophy, T. J., Am.J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated byreference in their entirety]. Excessive or unregulated TNF-α productionhas been implicated in mediating or exacerbating a number of undesirablephysiological conditions such as diseases including osteoarthritis, andother arthritic conditions; septic shock, endotoxic shock, respiratorydistress syndrome and bone resorption diseases since TNF-α alsoparticipates in the onset and progress of autoimmune diseases, PDE4inhibitors may find utility as therapeutic agents for rheumatoidarthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1,211-214 (1995) and ibid., 244-248 herein incorporated by reference intheir entirety].

Strong interest in drugs capable of selective inhibition of PDE 4 is dueto several factors. Tissue distribution of PDE-4 suggests thatpathologies related to the central nervous and immune systems could betreated with selective PDE-4 inhibitors. In addition, the increase inintracellular cAMP concentration, the obvious biochemical consequence ofPDE-4 inhibition, has been well characterized in immuno-competent cellswhere it acts as a deactivating signal.

Recently the PDE4 family has grown to include four subtypes—PDE4A toPDE4D, each encoded by a distinct gene (British Journal of Pharmacology;1999; v. 128; p. 1393-1398), herein incorporated by reference in itsentirety.

It has been demonstrated that increasing cAMP levels within these cellsresults in suppression of cell activation, which in turn inhibits theproduction and release of pro-inflammatory cytokines such as TNF-α.Since eosinophilis are believed to be a critical pro-inflammatory targetfor asthma, identification of the expression of the PDE-4 gene family ineosinophils led to the PDE-4 as a potential therapeutic target forasthma.

The usefulness of several PDE-4 inhibitors, unfortunately, is limiteddue to their undesirable side effect profile which include nausea andemesis (due to action on PDE-4 in the central nervous system) andgastric acid secretion due to action on PDE-4 in parietal cells in thegut. Barnette, M. S., Grous, M., Cieslinsky, L. B., Burman, M.,Christensen, S. B., Trophy, T J., J. Pharmacol. Exp. Ther., 273,1396-1402 (1995) herein incorporated by reference in their entirety. Oneof the earliest PDE-4 inhibitors, Rolipram™, was withdrawn from clinicaldevelopment because of its severe unacceptable side effect profile.Zeller E. et. al., Pharmacopsychiatr., 17, 188-190 (1984) hereinincorporated by reference in its entirety. The cause of severe sideeffects of several PDE-4 inhibitor molecules in human clinical trialshas recently become apparent.

There exist two binding sites on mammalian PDE-4 at which inhibitormolecules may bind. Also PDE-4 exists in two distinct forms whichrepresent different conformations. They are designated as High affinityRolipram binding site PDE-4H and Low affinity Rolipram binding sitePDE-4L [Jacobitz, S., McLaughlin, M. M., Livi, G. P., Burman, M.,Trophy, T. J., Mol. Pharmaco., 50, 891-899 (1996) herein incorporated byreference in their entirety]. It was shown that certain side effects(vomiting and gastric acid secretion) are associated with inhibition ofPDE-4H whereas some beneficial actions are associated with PDE-4Linhibition. It was also found that human recombinant PDE-4 exists in 4isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J. R., TrendsPharmacol. Sci., 17, 294-298 (1996) herein incorporated by reference inits entirety]. Accordingly, compounds displaying more PDE-4D isoenzymeselectivity over the A, B or C are found to have fewer side effects thanRolipram [Hughes. B et. al., Br. J. Pharmacol. 1996, 118, 1183-1191herein incorporated by reference in their entirety]. Therefore,selective inhibitors of PDE-4 isozymes would have therapeutic effects ininflammatory diseases such as asthma and other respiratory diseases.

Although several research groups all over the world are working to findhighly selective PDE-4 isozyme inhibitors, so far success has beenlimited. Various compounds have shown PDE-4 inhibition.

SmithKline Beecham's “Ariflo” which has the Formula A, Byk Gulden'sRoflumilast which has the Formula D and Bayer's Bay-19-8004 which hasthe Formula E have reached advanced stage of human clinical trials.Other compounds which have shown potent PDE-4 inhibitory activityinclude Celltech's CDP-840 of the Formula B, Schering Plough's D-4418 ofthe Formula C, Pfizer's 5CP-220,629 which has the Formula F, ParkeDavis's PD-168787 which has the Formula G and Wyeth's Filaminast whichhas the Formula H. However, recently due to efficacy and side effectsproblems, Ariflo, CDP-840 and Bay-19-8004 were discontinued fromclinical trials as a treatment for asthma. Other compounds of theFormulae C and F are presently undergoing phase-1 clinical trials.

During the course of our research aimed at the development of novelanti-asthmatic compounds having potential PDE4 inhibitory activity, wehave filed a WTO patent application in India bearing No. 922/MUM/2002dated Oct. 23, 2002 and PCT application No PCT/IB03/04442 dated Oct. 8,2003 herein incorporated by reference in their entirety for a novelseries of tricyclic compounds useful for the treatment of inflammatoryand allergic disorders

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel heterocyclic compoundsof the general Formula

wherein:

-   R¹, R² and R³ may be same or different and are independently    selected for each occurrence from the groups consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic group, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, formyl, acetyl, halogen, protecting groups,    —C(O)—R^(a), —C(O)O—R^(a), —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a),    —S(O)_(q)—NR^(a)R^(a), —NR^(a)R^(a), —OR^(a), —SR^(a) or when two R³    substitutents ortho to each other, may be joined to a form a    saturated or unsaturated 3-7 membered cyclic ring which may    optionally include up to two heteroatoms which may be same or    different selected from O, NR^(a) or S;-   wherein R⁴ is —NR⁵R⁶; wherein R⁵ and R⁶ may be same or different and    are independently selected from the groups consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic ring, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, halogen, —C(O)—R^(a), —C(O)O—R^(a),    —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a), —S(O)_(q)—NR^(a)R^(a),    —C(═NR^(a))—R^(a), —C(═NR^(a))—NR^(a)R^(a), —C(═S)—NR^(a)R^(a),    —C(═S)—R^(a), —N═C(R^(a)R^(a)), —NR^(a)R^(a), —OR^(a), —SR^(a),    protecting groups or R⁵ and R⁶ to each other may be joined to a form    a saturated or unsaturated 3-7 membered cyclic ring, which may    optionally include up to two heteroatoms which may be same or    different selected from O, NR^(a) or S;-   Ar is selected from the group consisting of substituted or    unsubstituted aryl, substituted or unsubstituted arylalkyl,    substituted or unsubstituted heterocyclic ring and substituted or    unsubstituted heteroaryl ring;-   Preferably Ar is optionally substituted phenyl, optionally    substituted benzyl, optionally substituted pyrimidine, optionally    substituted pyridyl selected from 4-pyridyl, 3-pyridyl and 2-pyridyl    or optionally substituted pyridyl-N-oxide selected from    4-pyridyl-N-oxide, 3-pyridyl-N-oxide and 2-pyridyl-N-oxide in which    optional substituents (one or more) may be same or different and are    independently selected from the groups consisting of hydrogen,    hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or    unsubstituted alkylcarbonyl, substituted or unsubstituted    alkylcarbonyloxy, substituted or unsubstituted amino or mono or di    substituted or unsubstituted alkylamino-   X is selected from the group consisting of O, S(O)_(q) and NR^(a);-   Y is selected from the group consisting of —C(O)NR⁷, —NR⁷S(O)_(q),    —S(O)_(q)NR⁷ and —NR⁷C(O);-   R⁷ is selected from the group consisting of hydrogen, substituted or    unsubstituted alkyl, hydroxyl, —OR^(a), substituted or unsubstituted    aryl, and substituted or unsubstituted heterocyclic ring;-   wherein P is chosen from O and S;-   wherein m represents 0-3;-   wherein n represents 1-4;-   wherein q represents 0,1 or 2;-   with the proviso that R⁴ is not NH₂;-   wherein R^(a) is selected from the group consisting of hydrogen,    substituted or unsubstituted alkyl, substituted or unsubstituted    alkenyl, substituted or unsubstitued alkynyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted    cycloalkylakyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted aryl, substituted or unsubstituted    arylalkyl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocyclic ring, substituted or unsubstituted    heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,    nitro, —OH, cyano, formyl, acetyl, halogen, protecting groups,    —C(O)—R^(a), —C(O)O—R^(a), —C(O)NR^(a)R^(a), —S(O)_(q)—R^(a),    —S(O)_(q)—NR^(a)R^(a), —NR^(a)R^(a), —OR^(a) or —SR^(a);-   and their analogs, their tautomers, their regioisomers, their    stereoisomers, their enantiomers, their diastereomers, their    polymorphs, their pharmaceutically acceptable salts, their N-oxides,    their pharmaceutically acceptable solvates and their pharmaceutical    compositions containing them or a pharmaceutical acceptable salts    thereof.

The present invention also relates to a process for the preparation ofthe above said novel heterocyclic compounds of the Formula (1) asdefined above. The compounds of general Formula (1) more particularly,down regulate or inhibit the production of TNF-α as they are PDE4inhibitors and therefore are useful in the treatment of variety ofallergic and inflammatory diseases including asthma, chronic bronchitis,atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis,rheumatoid arthritis, septic shock, diabetes, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. The compounds of the present invention are particularly usefulfor the treatment of asthma and chronic obstructive pulmonary disease(COPD).

Further prefered are when the substituents in the ‘substituted alkyl’,‘substituted alkoxy’ ‘substituted alkenyl’ ‘substituted alkynyl’‘substituted cycloalkyl’ ‘substituted cycloalkylalkyl’ ‘substitutedcycloalkenyl’ ‘substituted arylalkyl’ ‘substituted aryl’ ‘substitutedheterocyclic ring’, ‘substituted heteroaryl ring,’ ‘substitutedheteroarylalkyl’, ‘substituted heterocyclylalkyl ring’, ‘substitutedamino’, ‘substituted alkoxycarbonyl’, ‘substituted cyclic ring’‘substituted alkylcarbonyl’, ‘substituted alkylcarbonyloxy’ and may bethe same or different which one or more are selected from the groupssuch as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O),thio(═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedamino, substituted or unsubstituted heteroaryl, ‘substitutedheterocyclylalkyl ring’ substituted or unsubstituted heteroarylalkyl,substituted or unsubstituted heterocyclic ring, substituted orunsubstituted guanidine, —COOR^(x), —C(O)R^(x), —C(S)R^(x),—C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), —(═N—N(R^(x))R^(y)),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), —ONO₂,

-   wherein R^(x), R^(y) and R^(z) in each of the above groups can be    hydrogen atom, substituted or unsubstituted alkyl, substituted or    unsubstituted alkoxy, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    aryl, substituted or unsubstituted arylalkyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,    substituted or unsubstituted amino, substituted or unsubstituted    heteroaryl, ‘substituted heterocyclylalkyl ring’ substituted or    unsubstituted heteroarylalkyl, substituted or unsubstituted    heterocyclic ring,

Further prefered is where R¹ is unsubstituted alkyl.

Further prefered is where R¹ is methyl.

Further prefered is where R¹ is substituted alkyl.

Further prefered is where R¹ is —CHF₂.

Further prefered is where P is O.

Further prefered is where X is O, N—CH₃, S.

Further prefered is where Y is —C(O)NH.

Further prefered is where Ar is selected from the group consisting ofsubstituted or unsubstituted 4-pyridyl; substituted or unsubstituted4-pyridyl-N-oxide; substituted or unsubstituted 3-pyridyl.

Further prefered is where said Ar substituent is halogen.

Further prefered is where said Ar substituent is chloro.

Further prefered is where Ar is selected from the group consisting of

Further prefered is where Ar is

Further prefered is when m=0, n=1 and R⁴ is selected from the groupconsisting of

Further prefered is when m=0, n=1 and where R⁴ is selected from thegroup consisting of

The present invention specifically excludes the following compound:

DETAILED DESCRIPTION OF THE INVENTION

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

The term “alkenyl” refers to aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl(allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl and the like.

The term “alkynyl” refers to straight or branched chain hydrocarbylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl, propynyl, butnyl and the like.

The term “alkoxy” denotes alkyl group as defined above attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are —OCH₃, —OC₂H₅ and the like.

The term “alkylcarbonyl” denotes alkyl group as defined above attachedvia carbonyl linkage to the rest of the molecule. Representativeexamples of those groups are —C(O)CH₃, —C(O)C₂H₅ and the like.

The term “alkoxycarbonyl” denotes alkoxy group as defined above attachedvia carbonyl linkage to the rest of the molecule. Representativeexamples of those groups are —C(O)—OCH₃, —C(O)—OC₂H₅ and the like.

The term “alkylcarbonyloxy” denotes alkylcarbonyl group as defined aboveattached via oxygen linkage to the rest of the molecule. Representativeexamples of those groups are —O—C(O)CH₃, —O—C(O)C₂H₅ and the like.

The term “alkylamino” denotes alkyl group as defined above attached viaamino linkage to the rest of the molecule. Representative examples ofthose groups are —NH₂CH₃, —NH(CH₃)₂, —N(CH₃)₃ and the like.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups bridged cyclicgroup or sprirobicyclic groups e.g sprio (4,4) non-2-yl.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms directlyattached to alkyl group which are then attached to the main structure atany carbon from alkyl group that results in the creation of a stablestructure such as cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl,and the like.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms with at leastone carbon-carbon double bond such as cyclopropenyl, cyclobutenyl,cyclopentenyl and the like.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,biphenyl and the like.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅, —C₂H₅C₆H₅ andthe like.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical may be optionally oxidized to various oxidation states. Inaddition, the nitrogen atom may be optionally quaternized; and the ringradical may be partially or fully saturated (i.e., heteroaromatic orheteroaryl aromatic). Examples of such heterocyclic ring radicalsinclude, but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl,purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl,isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinylsulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl and thelike. The above includes substituted or unsubstituted pyridyl N-oxides.

The term “heteroaryl” refers to heterocyclic ring radical as definedabove. The heteroaryl ring radical may be attached to the main structureat any heteroatom or carbon atom that results in the creation of astable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedabove directly bonded to alkyl group. The heteroarylalkyl radical may beattached to the main structure at any carbon atom from alkyl group thatresults in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing 3-10 carbonatoms.

The term “protecting group” refers to carbobenzyloxy (CBZ) orTert.butyloxy carbonyl (BOC) and the like.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, thiamine, and the like; chiralbases like alkylphenylamine, glycinol, phenyl glycinol and the like,salts of natural amino acids such as glycine, alanine, valine, leucine,isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,proline, hydroxy proline, histidine, omithine, lysine, arginine, serine,and the like; quaternary ammonium salts of the compounds of inventionwith alkyl halides, alkyl sulphats like MeI, (Me)₂SO₄ and the like.non-natural amino acids such as D-isomers or substituted amino acids;guanidine, substituted guanidine wherein the substituents are selectedfrom nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substitutedammonium salts and aluminum salts. Salts may include acid addition saltswhere appropriate which are, sulphates, nitrates, phosphates,perchlorates, borates, hydrohalides, acetates, tartrates, maleates,citrates, fumarates, succinates, palmoates, methanesulphonates,benzoates, salicylates, benzenesulfonates, ascorbates,glycerophosphates, ketoglutarates and the like. Pharmaceuticallyacceptable solvates may be hydrates or comprise other solvents ofcrystallization such as alcohols.

The term inflammatory disorder generally refers to diseases andconditions induced by or associated with an excessive secretion of TNF-αand/or PDE-4. Another object of the invention is a method of treatinginflammatory diseases, disorders and conditions characterized by orassociated with an undesirable inflammatory immune response and diseasesand conditions induced by or associated with an excessive secretion ofTNF-α and/or PDE-4, which comprises administering to a subject atherapeutically effective amount of a compound according to Formula 1.

Another object of the invention is a method of treating inflammatoryconditions and immune disorders in a subject in need thereof whichcomprises administering to said subject a therapeutically effectiveamount of a compound according to Formula 1.

Preferred inflammatory disorders are chosen from the group consisting ofasthma, bronchial asthma, chronic obstructive pulmonary disease,allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoidarthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis,Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis,respiratory distress syndrome, rhematoid spondylitis, osteoarthritis,gouty arthritis, uteltis, allergic conjunctivitis, inflammatory bowelconditions, ulcerative coalitis, eczema, atopic dermatitis and chronicinflammation. Further preferred are allergic inflammatory conditions.

Further preferred inflamatory disorders include, but are not limited to,chronic abstructive pulmonary disease (COPD) and asthma.

Further preferred are inflammatory conditions and immune disordersselected from the group consisting of inflammatory conditions or immunedisorders of the lungs, joints, eyes, bowels, skin and heart.

Further preferred are inflammatory conditions chosen from the groupconsisting of bronchial asthma, nepritis, and allergic rhinitis.

Another object of the invention is a method for abating inflammation inan affected organ or tissue including delivering to the organ or tissuea therapeutically effective amount of a compound represented by acompound according to Formula 1.

Another object of the invention is a method of treating diseases of thecentral nervous system in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to Formula 1.

Preferred diseases of the central nervous system are chosen from thegroup consisting of depression, amnesia, dementia, Alzheimers disease,cardiac failure, shock and cerebrovascular disease.

Another object of the invention is a method of treating insulinresistant diabetes in a subject in need thereof which comprisesadministering to said subject a therapeutically effective amount of acompound according to Formula 1.

“Treating” or “treatment” of a state, disorder or condition includes:

-   (1) preventing or delaying the appearance of clinical symptoms of    the state, disorder or condition developing in a mammal that may be    afflicted with or predisposed to the state, disorder or condition    but does not yet experience or display clinical or subclinical    symptoms of the state, disorder or condition;-   (2) inhibiting the state, disorder or condition, i.e., arresting or    reducing the development of the disease or at least one clinical or    subclinical symptom thereof; or-   (3) relieving the disease, i.e., causing regression of the state,    disorder or condition or at least one of its clinical or subclinical    symptoms.

The benefit to a subject to be treated is either statisticallysignificant or at least perceptible to the patient or to the physician.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a state, disorder orcondition, is sufficient to effect such treatment. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the mammal to be treated.

The four classic symptoms of acute inflammation are redness, elevatedtemperature, swelling, and pain in the affected area, and loss offunction of the affected organ.

Symptoms and signs of inflammation associated with specific conditionsinclude:

-   -   rheumatoid arthritis—pain, swelling, warmth and tenderness of        the involved joints; generalized and morning stiffness;    -   insulin-dependent diabetes mellitus—insulitis; this condition        can lead to a variety of complications with an inflammatory        component, including: retinopathy, neuropathy, nephropathy;        coronary artery disease, peripheral vascular disease, and        cerebrovascular disease;    -   autoimmune thyroiditis—weakness, constipation, shortness of        breath, puffiness of the face, hands and feet, peripheral edema,        bradycardia;    -   multiple sclerosis—spasticity, blurry vision, vertigo, limb        weakness, paresthesias;    -   uveoretinitis—decreased night vision, loss of peripheral vision;    -   lupus erythematosus—joint pain, rash, photosensitivity, fever,        muscle pain, puffiness of the hands and feet, abnormal        urinalysis (hematuria, cylinduria, proteinuria),        glomerulonephritis, cognitive dysfunction, vessel thrombosis,        pericarditis;    -   scleroderma—Raynaud's disease; swelling of the hands, arms, legs        and face; skin thickening; pain, swelling and stiffness of the        fingers and knees, gastrointestinal dysfunction, restrictive        lung disease; pericarditis, renal failure;    -   other arthritic conditions having an inflammatory component such        as rheumatoid spondylitis, osteoarthritis, septic arthritis and        polyarthritis—fever, pain, swelling, tenderness;    -   other inflammatory brain disorders, such as meningitis,        Alzheimer's disease, AIDS dementia encephalitis—photophobia,        cognitive dysfunction, memory loss;    -   other inflammatory eye inflammations, such as        retinitis—decreased visual acuity;    -   inflammatory skin disorders, such as, eczema, other dermatites        (e.g., atopic, contact), psoriasis, burns induced by UV        radiation (sun rays and similar UV sources)—erythema, pain,        scaling, swelling, tenderness;    -   inflammatory bowel disease, such as Crohn's disease, ulcerative        colitis—pain, diarrhea, constipation, rectal bleeding, fever,        arthritis;    -   asthma—shortness of breath, wheezing;    -   other allergy disorders, such as allergic rhinitis—sneezing,        itching, runny nose conditions associated with acute trauma such        as cerebral injury following stroke—sensory loss, motor loss,        cognitive loss;    -   heart tissue injury due to myocardial ischemia—pain, shortness        of breath;    -   lung injury such as that which occurs in adult respiratory        distress syndrome—shortness of breath, hyperventilation,        decreased oxygenation, pulmonary infiltrates;    -   inflammation accompanying infection, such as sepsis, septic        shock, toxic shock syndrome—fever, respiratory failure,        tachycardia, hypotension, leukocytosis;    -   other inflammatory conditions associated with particular organs        or tissues, such as nephritis (e.g.,        glomerulonephritis)—oliguria, abnormal urinalysis;    -   inflamed appendix—fever, pain, tenderness, leukocytosis;    -   gout—pain, tenderness, swelling and erythema of the involved        joint, elevated serum    -   and/or urinary uric acid;    -   inflamed gall bladder—abdominal pain and tenderness, fever,        nausea, leukocytosis;    -   chronic obstructive pulmonary disease—shortness of breath,        wheezing;    -   congestive heart failure—shortness of breath, rates, peripheral        edema;    -   Type II diabetes—end organ complications including        cardiovascular, ocular, renal, and peripheral vascular disease,        lung fibrosis-hyperventilation, shortness of breath, decreased        oxygenation;    -   vascular disease, such as atherosclerosis and restenosis—pain,        loss of sensation, diminished pulses, loss of function and        alloimmunity leading to transplant rejection—pain, tenderness,        fever.

Subclinical symptoms include without limitation diagnostic markers forinflammation the appearance of which may precede the manifestation ofclinical symptoms. One class of subclinical symptoms is immunologicalsymptoms, such as the invasion or accumulation in an organ or tissue ofproinflammatory lymphoid cells or the presence locally or peripherallyof activated pro-inflammatory lymphoid cells recognizing a pathogen oran antigen specific to the organ or tissue. Activation of lymphoid cellscan be measured by techniques known in the art.

“Delivering” a therapeutically effective amount of an active ingredientto a particular location within a host means causing a therapeuticallyeffective blood concentration of the active ingredient at the particularlocation. This can be accomplished, e.g., by local or by systemicadministration of the active ingredient to the host.

“A subject” or “a patient” or “a host” refers to mammalian animals,preferably human.

Some of the representative compounds according to the present inventionare specified below but should not construed to be limited thereto;

-   1.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-   2.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dimethylsulphonamido)-dibenzo[b,d]furan-1-carboxamide-   3.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethanesulphonamido)-dibenzo[b,d]furan-1-carboxamide-   4.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   5.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(3-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamide-   6.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   7.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-t-butylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   8.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   9.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   10.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide    sodium salt-   11.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(fur-2-yl-carboxamido)-dibenzo[b,d]furan-1-carboxamide-   12.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(cyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamide-   13.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dicyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamide-   14.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoroacetamido-dibenzo[b,d]furan-1-carboxamide-   15.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide-   16.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isobutyloxycarboxamido-dibenzo[b,d]furan-1-carboxamide-   17.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamide-   18.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopropylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide-   19.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide-   20.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-N,N-diethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide-   21.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopentylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide-   22. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-yl    carboxamido-dibenzo[b,d]furan-1-carboxamide-   23. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-yl    carboxamido-dibenzo[b,d]furan-1-carboxamide hydrochloride-   24. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(4-hydroxypiperidin-1-yl    carboxamido-dibenzo[b,d]furan-1-carboxamide-   25. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(morphol-4-yl    carboxamido-dibenzo[b,d]furan-1-carboxamide-   26. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isopropylamino    carboxamido-dibenzo[b,d]furan-1-carboxamide-   27. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-n-hexylamino    carboxamido-dibenzo[b,d]furan-1-carboxamide-   28. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylamino    carboxamido-dibenzo[b,d]furan-1-carboxamide-   29. N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methylamino    carboxamido-dibenzo[b,d]furan-1-carboxamide-   30.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-   31.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide    sodium salt-   31(a) N-(3,5 dichloro pyrid-4-gl)-4-diflouro methoxy-8-meth and    sulfonamido-[b,d]furan-1-carboxamide N-oxide-   32.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethanesulfonamido-dibenzo[b,d]furan-1-carboxamide-   33.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-N,N-dimethylaminosulfonamido-dibenzo[b,d]furan-1-carboxamide-   34.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   35.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(1-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamide-   36.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-cyclopropylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   37.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   38.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   39.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide    disodium salt-   40.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamide-   41. N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   42.    N1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   43. N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   44.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamide-   45.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(n-butylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamide-   46.    N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   47.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-N-oxide-   48.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxide-   49.    N-(pyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-   50.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamide-   51.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamide-   52.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide-   53.    N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide-   54.    N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-acetamido-9H-4-carbazolecarboxamide-   55.    N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphonamido-9H-4-carbazolecarboxamide-   56.    N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethanesulphonamido-9H-4-carbazolecarboxamide-   57.    N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-propionamido-9H-4-carbazolecarboxamide-   58.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide    disodium salt-   59.    N-(3,5-dichloropyrid-4-yl)-1-methoxy-6-acetamido-dibenzo[b,d]thiophene-4-carboxamide-   60.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide    sodium salt-   61.    N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamide    sodium salt    -   and pharmaceutically acceptable salts and N-oxides of the        foregoing where applicable.

The compounds according to the invention may be prepared by thefollowing processes. The symbols P, Ar, X, Y, R¹, R², R³ and R⁴ whenused in the below Formulae are to be understood to present those groupsdescribed above in relation to Formula (1) unless otherwise indicated.

The present invention discloses a process for the preparation ofcompounds of general Formula (1).

In one embodiment, the desired compounds of the Formula (1) wherein Y is—CONR⁷; R⁴ is —NR⁵R⁶; P, Ar, X, Y, R¹, R², R³, R⁵, R⁶ R⁷, m and n are asdescribed in the general description, can be synthesized from a commonintermediate of the Formula (16).

The common intermediate of the Formula (16) can be synthesized by usingthe general process described in synthetic scheme I.

In the above mentioned scheme a compound of the general Formula (10)wherein Z is a halogen, preferably a fluorine, is reacted with acompound of the general Formula (11) wherein W is a halogen, preferablybromine or iodine, under basic conditions (potassium salts in DMF orDMSO, NaH in DMF or DMSO and the like) to obtain the intermediate of thegeneral Formula (12). The intermediate of the general Formula (12) canbe cyclised using metal compound or metal catalysed coupling conditions(palladium acetate in DMF or glacial acetic acid, nickel catalyst inpyridine or DMF, tetrakistriphenylphosphinepalladium in DMF and thelike), preferably palladium acetate in DMF, to the tricyclicintermediate (13). The tricyclic intermediate of the general Formula(13) is then oxidized to the intermediate of the general Formula (14)using standard methods (such as sodium chlorite or potassiumpermanganate and the like) known in the literature. The intermediate ofthe general Formula (14) is then converted to the intermediate of thegeneral Formula (15), wherein Y is —CONR⁷, by reacting the appropriatelyactivated carboxylic acid (acid halide or mixed anhydride or activeester) intermediate of the general Formula (14) with the optionallysubstituted aryl or heteroaryl amines (ArNHR⁷) under appropriate basicconditions (NaH in DMF, diisopropylamine or triethylamine or pyridine inTHF and the like) reported in the literature. The intermediate of thegeneral Formula (15) is then reduced using conventional methods (raneynickel/hydrazine, iron/ammonium chloride, hydrogenation using Pd/C, andthe like) known in the literature to the intermediate of the generalFormula (16).

The intermediate of the general Formula (16) is then converted to thedesired compound of the general Formula (1) wherein Y is —CONR⁷, R⁴ is—NR⁵R⁶; P, Ar, X, Y, R¹, R², R³, R⁵, R⁶ R⁷ m and n are the same asdescribed in the general description, using the conventional methodsknown in the literature.

The desired compounds of the general Formula (1) obtained are thenconverted into their salts and/or the N-oxides by the action of m-chloroper benzoic acid or H2)2 and the like and, if desired, salts of thecompounds of the Formula (1) obtained are then converted into the freeform.

In another embodiment, the desired compounds of the Formula (1) whereinY is —CONR⁷; R⁴ is —NR⁵R⁶; P, Ar, X, Y, R¹, R², R³, R⁵, R⁶, R⁷, m and nare the same as described in the general description, can be synthesizedfrom a common intermediate of the Formula (16). The common intermediateof the Formula (16) can be synthesized by using the general processdescribed in synthetic scheme II.

In the above mentioned scheme a compound of the general Formula (17)wherein Z is a halogen, preferably a fluorine, and wherein W is also ahalogen, preferably bromine or iodine, is reacted with a compound of thegeneral Formula (18) wherein FG is CHO, COCH₃, CN or —COOR^(a),

under basic conditions (potassium salts in DMF or DMSO, NaH in DMF orDMSO and the like) to obtain the intermediate of the general Formula(19). The intermediate of the general Formula (19) can be cyclised usingmetal compound or metal catalysed coupling conditions, nickel chloride,palladium acetate and the like preferably palladium acetate, to thetricyclic intermediate (20). The tricyclic intermediate of the generalFormula (20) is then oxidized using KMnO₄, NaOCl₂ and the like to, if FGis CHO or COCH₃, or hydrolysed by using NaOH or H₂SO₄ to, if FG is CN or—COOR^(a), the intermediate of the general Formula (14) using methodsknown in the literature. The intermediate of the general Formula (14) isthen converted to the intermediate of the general Formula (15), whereinY is —CONR⁷, by reacting the appropriately activated carboxylic acid(acid halide or mixed anhydride or active ester) intermediate of thegeneral Formula (14) with the optionally substituted aryl or heteroarylamines (ArNHR⁷) under appropriate basic conditions such as NaH in DMF ortriethylamine and the like reported in the literature. The intermediateof the general Formula (15) is then reduced using the conventionalmethods known in the literature (palladium chloride or Raney nickel) tothe intermediate of the general Formula (16).

The intermediate of the general Formula (16) is then converted to thedesired compound of the general Formula (1) wherein Y is —CONR⁷, R⁴ is—NR⁵R⁶; P, Ar, X, Y, R¹, R², R³, R⁵, R⁶, R⁷, m and n are the same asdescribed in the general description, using conventional methods knownin the literature.

The desired compounds of the general Formula (1) obtained are thenconverted into their salts and/or the N-oxides m-chloro per benzoic acidor H₂O₂ and the like and, if desired, salts of the compounds of theFormula (1) obtained are then converted into the free form.

In yet another embodiment, the desired compounds of the Formula (1)wherein Y is —CONR⁷, R⁴ is —NHCOCH₃, n=1; and P, Ar, X, Y, R¹, R², R³,R⁵, R⁶ R⁷ and m are the same as described in the general description,can be synthesized as in scheme III, Further the R⁴ wherein R⁴ is—NHCOCH₃ can be converted to, —NR⁵R⁶ using the methods known in theliterature.

In the above mentioned scheme a compound of the Formula (21) wherein Zis a halogen, preferably a fluorine, is reacted with a compound of thegeneral Formula (22) under basic conditions (potassium salts in DMF orDMSO, NaH in DMF or DMSO and the like) to obtain the intermediate of thegeneral Formula (23). The intermediate of the general Formula (23) isthen reduced to the intermediate of the general Formula (24) usingstandard reducing agents such as raney nickel/hydrazine or palladium oncarbon in hydrogen atmosphere. The intermediate of the general Formula(24) is then cyclised to the tricyclic intermediate of the generalFormula (25) by diazotization followed by standard coupling methods(cuprous oxide in 0.1N sulfuric acid, copper in DMSO). The acetyl groupof tricyclic intermediate of the general Formula (25) is then convertedto the acetamido group using Beckmann rearrangement to obtain theintermediate of the general Formula (26). The intermediate of thegeneral Formula (26) is formylated using standard formylating conditionssuch as dichloromethyl methyl ether in tin (IV) chloride and the like toobtain the intermediate of the general Formula (27). The intermediate ofthe general Formula (27) is then oxidized using KMnO₄ or NaOCl₂ to theintermediate of the general Formula (28) using standard methods known inthe literature. The intermediate of the general Formula (28) is thenconverted to the desired compound of the general Formula (1), wherein Yis —CONR⁷, R⁴ is —NHCOCH₃, n=1; and P, Ar, X, Y, R¹, R², R³, R⁵, R⁶ R⁷and m are the same as described in the general description, by reactingthe appropriately activated carboxylic acid (acid halide or mixedanhydride or active ester) intermediate of the general Formula (28) withthe optionally substituted aryl or heteroaryl amines (ArNHR⁷) usingconventional methods known in the literature. Further the R⁴ wherein R⁴is —NHCOCH₃ can be converted to, —NR⁵R⁶ using the methods known in theliterature

The desired compounds of the Formula (1) obtained are then convertedinto their salts and/or the N-oxides and, if desired, salts of thecompounds of the Formula (1) obtained are then converted into the freeform.

The N-oxidation is carried out in a manner likewise familiar to theperson of ordinary skill in the art, e.g with the aid ofm-chloroperoxybenzoic acid in dichloromethane at room temperature. Theperson of ordinary skill in the art is familiar with the reactionconditions which are necessary for carrying out the process on the basisof his knowledge.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuum andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g in a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecepitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification or by acidifying into the free compounds which, in turn canbe converted into salts.

In general, the ethereal solvents used in the above described processesfor the preparation of compounds of the Formula (1) are selected fromdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether,1,4 dioxane and the like. The chlorinated solvent which may be employedmay be selected from dichloromethane, 1,2-dichloroethane, chloroform,carbontetrachloride and the like. The aromatic solvents which may beemployed may be selected from benzene and toluene. The alchoholicsolvents which may be employed may be selected from methanol, ethanol,n-propanol, iso propanol, tert-butanol and the like. The aproticsolvents which may be employed may be selected fromN,N-dimethylformamide, dimethyl sulfoxide and the like.

In general, the compounds prepared in the above described processes areobtained in pure form by using well known techniques such ascrystallization using solvents such as pentane, diethyl ether, isopropylether, chloroform, dichloromethane, ethyl acetate, acetone, methanol,ethanol, isopropanol, water or their combinations, or columnchromatography using alumina or silica gel and eluting the column withsolvents such as hexane, petroleum ether (pet.ether), chloroform, ethylacetate, acetone, methanol or their combinations.

Various polymorphs of a compound of general Formula (1) forming part ofthis invention may be prepared by crystallization of compound of Formula(1) under different conditions. example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures, various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe NMR spectroscopy, IR spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The present invention provides novel heterocyclic compounds, theiranalogs, their tautomers, their regioisomers, their stereoisomers, theirenantiomers, their diastreomers, their polymorphs, theirpharmaceutically acceptable salts, their appropriate N-oxides and theirpharmaceutically acceptable solvates.

The present invention also provides pharmaceutical compositions,containing compounds of general Formula (1) as defined above, theirderivatives, their analogs, their tautomeric forms, their stereoisomers,their polymorphs, their enantiomers, their diasteromers, theirpharmaceutically acceptable salts or their pharmaceutically acceptablesolvates in combination with the usual pharmaceutically employedcarriers, diluents and the like. The pharmaceutical compositionsaccording to this invention can be used for the treatment of allergicdisorders.

It will be appreciated that some of the compounds of general Formula (1)defined above according to the invention can contain one or moreasymmetrically substituted carbon atoms. The presence of one or more ofthese asymmetric centers in the compounds of general Formula (1) cangive rise to stereoisomers and in each case the invention is to beunderstood to extend to all such stereoisomers, including enantiomersand diastereomers and their mixtures, including racemic mixtures. Theinvention may also contain E and Z geometrical isomers wherever possiblein the compounds of general Formula (1) which includes the single isomeror mixture of both the isomers

The pharmaceutical compositions may be in the forms normally employed,such as tablets, capsules, powders, syrups, solutions, suspensions andthe like and may contain flavorants, sweeteners etc. in suitable solidor liquid carriers or diluents, or in suitable sterile media to forminjectable solutions or suspensions. The active compounds of Formula (1)will be present in such pharmaceutical compositions in the amountssufficient to provide the desired dosage in the range as describedabove. Thus, for oral administration, the compounds of Formula (1) canbe combined with a suitable solid, liquid carrier or diluent to formcapsules, tablets, powders, syrups, solutions, suspensions and the like.The pharmaceutical compositions, may, if desired, contain additionalcomponents such as flavorants, sweeteners, excipients and the like. Forparenteral administration, the compounds of the Formula (1) can becombined with sterile aqueous or organic media to form injectablesolutions or suspensions. For example, solutions in sesame or peanutoil, aqueous propylene glycol and the like can be used as well asaqueous solutions of water-soluble pharmaceutically-acceptable acidaddition salts or salts with base of the compounds of Formula (1) Theinjectable solutions prepared in this manner can then be administeredintravenously, intraperitoneally, subcutaneously, or intramuscularly,with intramuscular administration being preferred in humans. Thecompounds can also be administered by inhalation when application withinthe respiratory tract is intended. Formulation of the present compoundsis especially significant for respiratory inhalation, wherein thecompound of Formula (1) is to be delivered in the form of an aerosolunder pressure. It is preferred to micronize the compound of Formula (1)after it has been homogenised, e.g., in lactose, glucose, higher fattyacids, sodium salt of dioctylsulfosuccinic acid or, most preferably, incarboxymethyl cellulose, in order to achieve a microparticle size of 5μm or less for the majority of particles. For the inhalationformulation, the aerosol can be mixed with a gas or a liquid propellantfor dispensing the active substance. An inhaler or atomizer or nebulizermay be used. Such devices are known. See, e.g., Newman et al., Thorax,1985, 40:61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92;incorporated herein by reference in their entirety. A Bird nebulizer canalso be used. See also U.S. Pat. Nos. 6,402,733; 6,273,086; and6,228,346, incorporated herein by reference in their entirety. Thecompound of the structure (1) for inhalation is preferably formulated inthe form of a dry powder with micronized particles. The compounds of theinvention may also be used in a metered dose inhaler using methodsdisclosed in U.S. Pat. No. 6,131,566, incorporated herein by referencein its entirety.

In addition to the compounds of Formula (1) the pharmaceuticalcompositions of the present invention may also contain or beco-administered with one or more known drugs selected from otherclinically useful therapeutic agents.

The invention is explained in detail in the examples given below whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention. The Examples aretabularized in Table I, which follows.

General Structural of formula (1) Ex. No. P X Y Ar m n R¹ R² R³ R⁴ Salt 1. O O —CONH

0 1 CH₃ — —

—  2. O O —CONH

0 1 CH₃ — —

—  3. O O —CONH

0 1 CH₃ — —

—  4. O O —CONH

0 1 CH₃ — —

—  5. O O —CONH

0 1 CH₃ — —

—  6. O O —CONH

0 1 CH₃ — —

—  7. O O —CONH

0 1 CH₃ — —

—  8. O O —CONH

0 1 CH₃ — —

—  9. O O —CONH

0 1 CH₃ — —

— 10. O O —CONH

0 1 CH₃ — —

Na 11. O O —CONH

0 1 CH₃ — —

— 12. O O —CONH

0 1 CH₃ — —

— 13. O O —CONH

0 1 CH₃ — —

— 14. O O —CONH

0 1 CH₃ — —

— 15. O O —CONH

0 1 CH₃ — —

— 16. O O —CONH

0 1 CH₃ — —

— 17. O O —CONH

0 1 CH₃ — —

— 18. O O —CONH

0 1 CH₃ — —

— 19. O O —CONH

0 1 CH₃ — —

— 20. O O —CONH

0 1 CH₃ — —

— 21. O O —CONH

0 1 CH₃ — —

— 22. O O —CONH

0 1 CH₃ — —

— 23. O O —CONH

0 1 CH₃ — —

HCl 24. O O —CONH

0 1 CH₃ — —

— 25. O O —CONH

0 1 CH₃ — —

— 26. O O —CONH

0 1 CH₃ — —

— 27. O O —CONH

0 1 CH₃ — —

— 28. O O —CONH

0 1 CH₃ — —

— 29. O O —CONH

0 1 CH₃ — —

— 30. O O —CONH

0 1 CHF₂ — —

—  30a O O —CONH

0 1 CHF₂ — —

— 31. O O —CONH

0 1 CHF₂ — —

Na 32. O O —CONH

0 1 CHF₂ — —

— 33. O O —CONH

0 1 CHF₂ — —

— 34. O O —CONH

0 1 CHF₂ — —

— 35. O O —CONH

0 1 CHF₂ — —

— 36. O O —CONH

0 1 CHF₂ — —

— 37. O O —CONH

0 1 CHF₂ — —

— 38. O O —CONH

0 1 CHF₂ — —

— 39. O O —CONH

0 1 CHF₂ — —

2Na 40. O O —CONH

0 1 CHF₂ — —

— 41. O O —CONH

0 1 CH₃ — —

— 42. O O —CONH

0 1 CH₃ — —

— 43. O O —CONH

0 1 CH₃ — —

— 44. O O —CONH

0 1 CH₃ — —

— 45. O O —CONH

0 1 CH₃ — —

— 46. O O —CONH

0 1 CH₃ — —

— 47. O O —CONH

0 1 CH₃ — —

— 48. O O —CONH

0 1 CH₃ — —

— 49. O O —CONH

0 1 CH₃ — —

— 50. O O —CONH

0 1 CH₃ — —

— 51. O O —CONH

0 1 CH₃ — —

— 52. O O —CONH

0 1 CH₃ — —

— 53. O O —CONH

0 1 CH₃ — —

— 54. O N—CH₃ —CONH

0 1 CH₃ — —

— 55. O N—CH₃ —CONH

0 1 CH₃ — —

— 56. O N—CH₃ —CONH

0 1 CH₃ — —

— 57. O N—CH₃ —CONH

0 1 CH₃ — —

— 58. O O —CONH

0 1 CHF₂

2Na 59. O S —CONH

0 1 CH₃ — —

— 60. O O —CONH

0 1 CHF₂ — —

Na 61. O O —CONH

0 1 CHF₂ — —

Na

The following intermediates have been used to synthesize therepresentative examples of the compounds of the invention.

Intermediate 1 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-aminodibenzo[b,d]furan-1-carboxamide

Step 1: 2-Bromoisovanillin

Isovanillin (5 gm, 0.033 mol) was dissolved in glacial acetic acid (30ml). Anhydrous sodium acetate (5.4 gm) was added to the above solutionfollowed by powdered iron (0.15 gm). The system was flushed thoroughlywith nitrogen. A solution of bromine (5.79 gm, 0.0362 mol) in glacialacetic acid (10 ml) was added to the above stirred suspension at roomtemperature over a period of 15 min. The reaction mixture was stirred atroom temperature for 45 min. The reaction mixture was poured intoaqueous 2% sodium bisulfite (200 ml) and stirred for 10 min. Theprecipitate was filtered washed with water (100 ml), and dried to obtain3.5 gm of 2-bromoisovanillin as white powder mp: (200-202° C.).

IR (KBr) 3233, 2990, 2891, 2844, 1669, 1593, 1564, 1494, 1463, 1286,1238, 1205, 1019, 987, 805, 786 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 3.99 (s,3H), 6.13 (s, 1H), 6.89 (d, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.4 Hz), 10.23(s, 1H).

Step 2: 2-Bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde

To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) indry DMSO (10 ml) was added a solution of 2-bromoisovanillin (5.0 gm,0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm,0.0260 mol) in DMSO (5 ml) was added to the above suspension and thereaction mixture was stirred at 140° C. for 4 h. The reaction mixturewas cooled to room temperature and the contents were poured into water(150 ml) and extracted with ethyl acetate (50 ml×3). The organicextracts were combined and washed with 1N sodium hydroxide (25 ml×2),water and brine and dried over anhydrous sodium sulfate. The driedorganic layer was concentrated in vacuo and the residue was purified bysilica-gel column chromatography using 20% ethyl acetate-petroleum etheras the eluent to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehydeas a pale yellow solid (5.0 gm) mp:132-140° C.

IR (KBr) 3084, 2874, 1689, 1584, 1506, 1486, 1348, 1285, 1253, 1234,1114, 1025, 848, 815, 747 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 3.86 (s, 3H),6.89 (d, 2H, J=7.2 Hz), 7.07 (d, 1H, J=9.0 Hz), 7.92 (d, 1H, J=8.4 Hz),8.17 (d, 2H, J=9.0 Hz), 10.24 (s, 1H).

Step 3: 4-methoxy-8-nitro-1-formyl dibenzo[b,d]furan

2-Bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde (3.5 gm, 0.0087 mol),anhydrous sodium carbonate (1.125 gm, 0.0106 mol) and palladium (II)acetate (0.19 gm, 0.0008 mol), in dimethylacetamide (15 ml) are heatedand stirred under nitrogen at 170° C. for 2 h. Water (90 ml) is added tothe cooled reaction mixture. The precipitated solid is collected byfilteration and washed with 5% hydrochloric acid followed by water. Theproduct was obtained as a yellow solid (3.4 gm).

IR (KBr) 3115, 2925, 2856, 1682, 1609, 1576, 1522, 1343, 1295, 1076,846, 829 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 4.13 (s, 3H), 7.53 (d, 1H, J=9.0Hz), 8.01 (d, 1H, J=9.0 Hz), 8.16 (d, 1H, J=9.0 Hz), 8.48 (dd, 1H, J=9.0Hz, 3.0 Hz), 9.79 (d, 1H, J=3.0 Hz), 10.1 (s, 1H).

Step 4: 4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid

4-methoxy-8-nitro-1-formyl dibenzo[b,d]furan (1.1 gm, 0.0034 mol) inacetone (5 ml) was heated to 60-70° C. for 10 min. To the abovesuspension was added dropwise a hot solution of potassium permanganate(1.07 gm, 0.0068 mol) in water:acetone (1:3) (15 ml) for 10 min. Thereaction was heated to 60-70° C. for 10 min., cooled to room temperatureand filtered. The residue washed with acetone and the filterate wasextracted with 10% sodium hydroxide solution. Acidification, followed byfilteration and washing of the precipitate yielded4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (0.6 gin) as whitesolid; mp: 178° C. (dec.)

IR (KBr) 3467, 2942, 1711, 1694, 1633, 1610, 1574, 1522, 1453, 1417,1344, 1278, 1069, 846, 826, 743 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 4.08 (s,3H), 7.36 (d, 1H, J=8.4 Hz), 7.98 (d, 1H, J=9.0 Hz), 8.07 (d, 1H, J=8.4Hz), 8.44 (dd, 1H, J=9.0 Hz, 2.7 Hz), 9.79 (d, 1H, J=2.4 Hz),

Step 5a: 4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid chloride

A suspension of 4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid(150 mg, 0.52 mmol) (from step 4) in a mixture of benzene (2 ml) andfreshly distilled thionyl chloride (2 ml) was heated to refluxtemperature for 4 h. The excess thionyl chloride was removed undervacuum to get the corresponding acid chloride which was subjected thenext reaction as such.

Step 5b: N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitrodibenzo[b,d]furan-1-carboxamide

To a pre-washed suspension of sodium hydride (52 mg, 2.5 equiv., 1.3mmol, 60% oil dispersion) in DMF (2 ml) was added drop wise a solutionof 4-amino-3,5-dichloropyridine (93 mg, 0.52 mmol) in DMF (2 ml) at −10°C. A pre-cooled solution of above acid chloride (0.52 mmol) (from step5a) in THF (2 ml) was added, all at once, to the reaction mixture andthe contents were stirred at −10° C. for 30 min. The reaction wasquenched with brine, diluted with water and filtered to give a crudesolid which was washed with ethanol to giveN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamideas a white solid (80 mg); mp: 315-317° C.

IR (KBr): 3245, 3092, 2845, 1662, 1614, 1581, 1554, 1519, 1483, 1461,1439, 1391, 1337, 1282, 1205, 1181, 1067 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ4.12 (s, 3H), 7.48 (d, 1H, J=8.1 Hz), 8.03 (d, 1H, J=8.1 Hz), 8.06 (d,1H, J=8.4 Hz), 8.44 (dd, 1H, J=7.2 Hz), 8.81 (s, 2H). 9.43 (d, 1H, J=1.2Hz), 10.95 (s, 1H).

Step 6:N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

Iron powder (467 mg, 8.35 mmol) and ammonium chloride (742 mg, 13.5mmol) were heated at 80° C. for 15 min.N-(3,5-pyrid-4-yl)-4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxamide(800 mg, 1.85 mmol) was suspended in methanol and allowed to trickledown into the above reaction mixture at reflux. The reaction wasrefluxed for 3 h and filtered hot. Methanol was evaporated, and thesolid was washed with water and taken directly without purification tosynthesize the following examples.

Intermediate 2 N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide

Step 1: 4-cyclopentoxy-3-hydroxy-benzaldehyde

A suspension of 3,4-dihydroxybenzaldehyde (5.0 gm, 0.0362 mol),anhydrous potassium carbonate (6.0 gm, 0.0434 mol) and cyclopentylbromide (6.5 gm, 0.0434 mol) in dry DMF (50 ml) was heated and stirredat 80° C. for 24 hrs. Reaction mixture was then cooled and diluted withwater (500 ml), acidified with 1N HCl and extracted with ethyl acetate(3×100 ml). The ethyl acetate extract was washed 5% sodium bicarbonateand brine and dried over anhydrous sodium sulfate. The dried extract onconcentration afforded a residue which was purified by silica gelchromatography using 10% ethyl acetate in petroleum ether as the eluentto provide 5.0 gm of the title product as white solid. mp: 87-89° C.

IR (KBr) 2964, 1670, 1605, 1580, 1500, 1463, 1358, 1271, 1122, 976, 806,748 cm⁻¹. ¹H NMR (300 MHz, CDCl₃) δ 1.65-2.04 (m, 8H), 4.93 (m, 1H),5.83 (s, 1H), 6.94 (d, 1H), 7.38-7.43 (m, 2H), 9.82 (s, 1H).

Step 2: 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde

4-cyclopentoxy-3-hydroxy-benzaldehyde (1.0 gm, 4.84 mmol) was dissolvedin glacial acetic acid (20 ml). Anhydrous sodium acetate (0.8 gm, 9.7mmol) was added to the above solution followed by powdered iron (0.022gm). The system was flushed thoroughly with nitrogen. A solution ofbromine (0.854 gm, 5.32 mmol) in glacial acetic acid (10 ml) was addedto the above stirred suspension at 15° C. over a period of 15 min. Thereaction mixture was stirred at 15° C. for 45 min. The reaction mixturewas poured into aqueous 2% sodium bisulfite (100 ml) and stirred for 10min. The precipitate was filtered washed with water (100 ml), and driedto obtain 800 mg of 2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde aswhite powder mp: 107-109° C.

¹H NMR (300 MHz, CDCl₃) δ 1.66-2.03 (m, 8H), 4.92 (m, 1H), 6.15 (s, 1H),6.90 (d, 1H), 7.54 (d, 1H), 10.25 (s, 1H).

Step 3: 2-bromo-4-cyclopentoxy-3-(p-nitrophenoxy)-benzaldehyde

To a stirred suspension of potassium fluoride (125 mg, 2.104 mmol) indry DMSO (2.5 ml) was added a solution of2-bromo-4-cyclopentoxy-3-hydroxy-benzaldehyde (500 mg, 1.754 mmol) inDMSO (2.5 ml). A solution of 4-fluoronitrobenzene (500 mg, 2.631 mmol)in DMSO (2.5 ml) was added to the above suspension and the reactionmixture was stirred at 140° C. for 6 h. The reaction mixture was cooledto room temperature and the contents were poured into water (100 ml) andextracted with ethyl acetate (50 ml×3). The organic extracts werecombined and washed with 1N sodium hydroxide (25 ml×2), water and brineand dried over anhydrous sodium sulfate. The dried organic layer wasconcentrated in vacuo to give 2-bromo-3-(p-nitrophenoxy)-4-methoxybenzaldehyde as a pale yellow solid (500 mg) mp: 115-117° C.

¹H NMR (300 MHz, CDCl₃) δ 1.18-1.23 (m, 2H), 1.39-1.53 (m, 4H),1.73-1.81 (m, 2H), 5.01 (m, 1H), 7.09 (dd, 2H), 7.43 (d, 1H), 7.87 (d,1H), 8.24 (dd, 2H), 10.13 (s, 1H).

Step 4: 4-cyclopentyloxy-8-nitro-1-formyl dibenzo[b,d]furan

Intermediate 2-bromo-4-cyclopentoxy-3-(p-nitrophenoxy)-benzaldehyde (500mg, 1.09 mmol), anhydrous sodium carbonate (150 mg, 1.325 mmol) andpalladium (II) acetate (25 mg, 0.096 mmol), in dimethylformamide (10 ml)are heated and stirred under nitrogen at 130° C. for 7 h. Water (90 ml)is added to the cooled reaction mixture and extracted with ethyl acetate(2×25 ml). The combined organic layer was washed with 5% hydrochloricacid followed by water and dried over anhydrous sodium sulfate to affordthe product as a yellow solid (200 mg). mp: 230-240° C.

¹H NMR (300 MHz, DMSO) δ 1.70 (m, 2H), 1.77-1.92 (m, 4H), 2.09 (m, 2H),5.25 (m, 1H), 7.53 (d, 1H), 8.05 (d, 1H), 8.14 (d, 1H), 8.51 (d, 1H),9.80 (s, 1H), 10.14 (s, 1H).

Step 5: 4-hydroxy-8-nitro-1-formyl dibenzo[b,d]furan

4-cyclopentyloxy-8-nitro-1-formyl dibenzo[b,d]furan (200 mg, 0.530 mol)was heated in HBr (47% in acetic acid) (5 ml) in glacial acetic acid (10ml) at 50° C. for 7-8 h. The reaction contents were poured in ice-water(200 ml) and extracted with ethyl acetate (3×50 ml). The combinedorganic layer was washed with saturated sodium bicarbonate, and waterand dried over anhydrous sodium sulfate. Removal of the organic solventin vacuo afforded the crude product as a white solid (150 mg). The crudewhite solid was used as such without further purification. mp: >270° C.

¹H NMR (300 MHz, DMSO) δ 7.28 (d, 1H), 8.01 (d, 1H), 8.04 (d, 1H), 8.50(d, 1H), 9.83 (s, 1H), 10.09 (s, 1H), 11.92 (s, 1H).

Step 6: 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d]furan

A suspension of 4-hydroxy-8-nitro-1-formyl dibenzo[b,d]furan (150 mg,0.485 mmol) and anhydrous potassium carbonate (200 mg, 1.455 mmol) indry DMF (5.0 ml) was stirred at 80° C. for 10 min. Chlorodifluoromethanegas was purged into the reaction mixture for 45 min. The reactionmixture was cooled, diluted with water (50 ml), and extracted with ethylacetate (3×25 ml). The combined organic layer was washed with water anddried over anhydrous sodium sulfate. Removal of the organic solvent invacuo afforded the product as a white solid (150 mg). mp: 245-248° C.

Step 7: 4-difluoromethoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid

4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d]furan (150 mg, 0.48 mmol)in acetone (20 ml) and water (5 ml) was heated to 60-70° C. for 10 min.To the above solution was added dropwise a solution of potassiumpermanganate (150 mg, 0.973 mmol) in water (5 ml) for 10 min. Thereaction was heated to 60-70° C. for 30 min., and filtered hot throughcelite bed. Acidification of the filterate resulted in a precipitatewhich on filteration and washing with water yielded4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (100 mg)as white solid; mp: >270° C.

¹H NMR (300 MHz, DMSO) δ 7.61 (t, 1H, J=72 Hz), 7.60 (d, 1H), 8.07 (d,1H), 8.13 (d, 1H), 8.52 (d, 1H), 9.77 (s, 1H), 13.80 (s, 1H).

Step 8:N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

A solution 4-difluoromethoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid(100 mg, 0.30 mmol), in a mixture of benzene (2 ml) and freshlydistilled thionyl chloride (2 ml) was heated to reflux temperature for 4h. The excess thionyl chloride was removed under vacuum to get thecorresponding acid chloride.

To a pre-washed suspension of sodium hydride (25 mg, 60% oil dispersion)in DMF (3 ml) was added dropwise a solution of4-amino-3,5-dichloropyridine (53 mg, 0.30 mmol) in DMF (2 ml) at −10° C.A pre-cooled solution of above acid chloride (0.30 mmol) in THF (5 ml)was added, all at once, to the reaction mixture and the contents werestirred at −10° C. for 30 min. The reaction was quenched with brine,diluted with water and filtered to give a crude solid which was purifiedby silica gel chromatography using 10% acetone in chloroform as theeluent to provide 100 mg ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamideas white solid. mp: >270° C.

IR (KBr): 3213, 2926, 1664, 1555, 1526, 1488, 1339, 1285, 1199, 1090,904, 823 cm−1. ¹H NMR (300 MHz, DMSO) δ 7.63 (t, 1H, J=72 Hz), 7.77 (d,1H), 8.09 (d, 1H), 8.13 (d, 1H), 8.52 (dd, 1H, J=9.3 Hz, 2.4 Hz), 8.86(s, 2H), 9.39 (d, 1H, J=2.7 Hz), 11.21 (s, 1H).

Step 9:N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

A mixture ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide(step 8) (100 mg), methanol (10 ml) and 10% Pd/C (10 mg) washydrogenated at 60 psi for 12 h. Filteration of the reaction mixtureover celite bed and removal of solvent methanol under reduced pressureaffordedN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamideas white solid. mp: >270° C.

IR (KBr): 3436, 3360, 3185, 2921, 1659, 1555, 1484, 1391, 1292, 1195,1133, 1055, 910, 811, 674 cm−1. ¹H NMR (300 MHz, DMSO) δ 5.14 (brs, 2H),6.86 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.53 (t, 1H, J=72 Hz), 7.46-7.51 (m,2H), 7.80 (d, 1H, J=9.0 Hz), 8.80 (s, 2H), 10.96 (s, 1H).

Intermediate 3N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide

Step 1: methyl-3-(2-bromo-4-nitroanilino)-4-methoxybenzoate

3-amino-4-methoxy methyl benzoate (3.5 gm, 0.0193 mol) (commercial) wasdissolved in DMF (20 ml) and added to a suspension of sodium hydride(60% dispersion) (1.54 gm, 0.0386 mol) in DMF (20 ml). The reactionmixture was stirred under nitrogen for 30 minutes at room temperature,followed by addition of a solution of 3-bromo-4-fluoro nitrobenzene(5.05 gm, 0.0231 mol) in DMF (20 ml) at 0° C. over a period of 10minutes. The reaction was stirred at room temperature for 18 hrs. Thereaction was then quenched with brine and diluted with ice cold water(500 ml) to get a precipitate which was filtered and dried to get thecrude product. The crude product was purified by column chromatographyusing 40% ethyl acetate in petroleum ether as eluent to get pure productas a yellow solid.

IR (KBr): 3363, 3103, 3005, 2952, 2951, 1720, 1600, 1581, 1506, 1492,1443, 1327, 1295, 1255, 1144, 1117, 1103, 1020, 1003, 824, 760, 743cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 3.83 (s, 3H), 3.85 (s, 3H), 6.50 (d, 1H,J=9.0 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.86 (s, 1H ), 8.01 (d, 1H, J=7.2Hz), 8.03 (d, 1H, J=7.2 Hz), 8.19 (s, 1H), 8.37 (s, 1H).

Step 2: methyl-1-methoxy-6-nitro-9H-4-carbazolecarboxylate

Methyl-3-(2-bromo-4-nitroanilino)-4-methoxybenzoate (3 gm, 0.0093 mol),anhydrous sodium carbonate (2.96 gm, 0.0275 mol) and palladium (II)acetate (1 gm, 0.0046 mol), in dimethylformamide (60 ml) were heated andstirred under nitrogen at 140° C. for 18 hr. The reaction mixture wascooled and filtered through celite bed. Water (90 ml) was added to thecooled reaction mixture. The precipitated solid was acidified andcollected by filtration and washed with water. The product was obtainedas a yellow solid (3.4 gm).

IR (KBr): 3404, 3133, 3017, 2964, 1724, 1626, 1615, 1571, 1513, 1461,1435, 1318, 1267, 1231, 1200, 1070, 920, 741 cm⁻¹. ¹H NMR (300 MHz,DMSO): δ 3.99 (s, 3H), 4.11 (s, 3H), 7.24 (d, 1H, J=8.7 Hz), 7.67 (d,1H, J=9.0 Hz), 8.01 (d, 1H, J=9.0 Hz), 8.34 (dd, 1H, J=8.7 and 2.4 Hz),9.95 (d, 1H, J=2.4 Hz), 12.57 (s, 1H).

Step 3: methyl-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxylate

Methyl-1-methoxy-6-nitro-9H-4-carbazolecarboxylate (1 gm, 0.0026 mol)was dissolved in DMF (10 ml) and added to a suspension of sodium hydride(104 mg, 0.0052 mol) in DMF (10 ml) at room temperature over a period of10 minutes. Solution of methyl iodide (549 mg, 0.0039 mol) in DMF (10ml) was added to the reaction mixture and it was stirred further for aperiod of 1 hr. The reaction was then quenched with brine and dilutedwith water. The precipitate obtained was acidified and then filtered toget a yellow solid.

IR (KBr): 3131, 2943, 2846, 1730, 1618, 1572, 1514, 1438, 1324, 1251,1136, 1068, 1017, 809, 740 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 3.97 (s, 3H),4.05 (s, 3H), 4.19 (s, 3H), 7.22 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=9.0Hz), 7.95 (d, 1H, J=9.0 Hz), 8.34 (dd, 1H, J=8.7 and 2.4 Hz), 9.90 (d,1H, J=2.4 Hz).

Step 4: 1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxylic acid

Methyl-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxylate (500 mg) wassuspended in methanol (15 ml) and added with 1 M NaOH (10 ml). Thereaction mixture was refluxed for 18 hrs. Methanol was evaporated andthe compound was diluted with water followed by addition of HCl. Theprecipitate was filtered to get a brown solid.

¹H NMR (300 MHz, DMSO): δ 4.06 (s, 3H), 4.23 (s, 3H), 7.24 (d, 1H, J=8.7Hz), 7.82 (d, 1H, J=9.0 Hz), 7.95 (d, 1H, J=9.0 Hz), 8.36 (dd, 1H, J=9.0and 2.4 Hz), 10.03 (d, 1H, J=2.4 Hz), 13.01 (brs, 1H).

Step 4a: 1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxy acid chloride

1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxylic acid (300 mg) wassuspended in freshly distilled thionyl chloride (2 ml) was heated toreflux temperature for 4 hr. The excess thionyl chloride was removedunder vacuum to get the corresponding acid chloride which was subjectedthe next reaction as such.

Step 5:N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxamide

To a pre-washed suspension of sodium hydride (100 mg, 2.5 equiv.,0.0025, 60% oil dispersion) in DMF (3 ml) was added drop wise a solutionof 4-amino-3,5-dichloropyridine (244 mg, 0.0015 mol) in DMF (3 ml) at−10° C. A pre-cooled solution of above acid chloride (from step 4a) inTHF (5 ml) was added, all at once, to the reaction mixture at −50° C.and the contents were stirred at −50° C. for 1 hr. The reaction wasquenched with brine, diluted with water and filtered to giveN-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxamideas a yellow solid (250 mg); mp: >250° C.

IR (KBr): 3432, 3199, 2936, 2841, 1662, 1575, 1513, 1479, 1398, 1323,1313, 1275, 1254, 1095, 1067, 1018, 809, 745 cm⁻¹. ¹H NMR (300 MHz,DMSO): δ 4.08 (s, 3H), 4.25 (s, 3H), 7.32 (d, 1H, J=8.4 Hz), 7.76-7.83(m, 2H), 8.36 (dd, 1H, J=9.0 and 2.4 Hz), 8.84 (s, 2H), 10.03 (d, 1H,J=2.4 Hz), 10.89 (s, 1H).

Step 6:N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide

N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-nitro-9H-4-carbazolecarboxamide(250 mg) was suspended in DMF (20 ml) and methanol (10 ml) and addedwith raney nickel (25 mg, 10% w/w) and reduced under pressure (60 psi)for 18 hrs at room temperature. The reaction mixture was filteredthrough celite and DMF was evaporated to get a green solid which waswashed with water to giveN-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide.Confirmed by ninhydrin. The compound was taken directly withoutpurification to synthesize the following example no 54, 55, 56 and 57

Representative compounds of the invention, which should not be construedas limiting in any way, are found at Table I General Structure ofFormula (1A).

EXAMPLE 1N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) was treated with methanesulfonylchloride (24 mg, 0.299 mol) in THF (10 ml) containing pyridine (23 mg,0.299 mmol) at 0° C. and allowed to warm to room temperature. Thereaction was stirred at room temperature for 30 min. THF was evaporatedand the residue was washed with saturated sodium bicarbonate solution,water. The solid obtained was purified by silica gel columnchromatography using 30% acetone-chloroform as eluent to obtain 30 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonylamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 315° C.

IR (KBr): 3272, 3147, 2925, 1661, 1607, 1490, 1393, 1313, 1288, 1145,1101, 810 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 2.91 (s, 3H), 4.07 (s, 3H),7.35 (d, 1H, J=8.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.73 (d, 1H, J=8.4 Hz),7.80 (d, 1H, J=8.4 Hz), 8.31 (s, 1H), 8.77 (s, 2H), 9.65 (s, 1H), 10.80(s, 1H).

Example 2 and 3 were synthesized using reaction conditions similar toExample 1 except for using the appropriate substituted sulfonyl chlorideinstead of methanesulfonyl chloride.

EXAMPLE 2N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dimethylsulphonamido)-dibenzo[b,d]furan-1-carboxamide

IR (KBr): 3370, 2922, 1675, 1608, 1483, 1278, 1147, 963, 899, 801, 701cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 2.65 (s, 6H), 4.07 (s, 3H), 7.33 (d, 1H,J=8.7 Hz), 7.43 (dd, 1H, J=8.7 and 1.8 Hz), 7.68 (d, 1H, J=8.7 Hz), 7.88(d, 1H, J=8.7 Hz), 8.31 (d, 1H, J=1.8 Hz), 8.77 (s, 2H), 9.82 (s, 1H),10.79 (s, 1H).

EXAMPLE 3N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethanesulphonamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 3H, J=7.2 Hz), δ 2.99 (q, 2H, J=7.5Hz), δ 4.07 (s, 3H), δ 7.36 (d, 1H, J=8.4 Hz), δ 7.41 (dd, 1H, J=8.7 Hzand J=2.4 Hz), δ 7.72 (d, 1H, J=8.7 Hz), δ 7.91 (d, 1H, J=8.4 Hz), δ8.32 (d, 1H, J=2.4 Hz), δ 8.77 (s, 2H), δ 9.73 (s, 1H), δ 10.80 (s, 1H).

IR (KBr) 3304, 2968, 2933, 1680, 1608, 1484, 1461, 1332, 1282, 1196,1143, 1101, 1022, 957, 810, 780 cm−1

EXAMPLE 4N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) was treated with acetyl chloride(22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (23 mg, 0.299mmol) at 0° C. and allowed to warm to room temperature. The reaction wasstirred at room temperature for 30 min. THF was evaporated and theresidue was washed with saturated sodium bicarbonate solution and water.The solid obtained was purified by silica gel column chromatographyusing 30% acetone-chloroform as eluent to obtain 25 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 252° C.

IR (KBr): 3271, 2961, 2925, 2852, 1660, 1607, 1542, 1499, 1468, 1392,1285, 1261, 1101, 1021, 805 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 2.01 (s, 3H),4.07 (s, 3H), 7.32 (d, 1H, J=8.4 Hz), 7.65 (d, 1H, J=8.4 Hz), 7.93 (m,2H), 8.41 (s, 1H), 8.76 (s, 2H), 10.06 (s, 1H), 10.76 (s, 1H).

Example 5, 6, 7, 8, 11, 12 and 13 were synthesized using reactionconditions similar to Example 4 except for using the appropriatesubstituted acid chloride instead of acetyl chloride.

EXAMPLE 5N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(3-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamide

IR (KBr): 3244, 2940, 1655, 1606, 1543, 1493, 1446, 1393, 1283, 1222,1199, 1099, 1022, 936, 810, 722, 670, 575 cm⁻¹. ¹H NMR (300 MHz, DMSO):δ 2.00 (m, 2H), 2.50 (t, 2H), 3.7 (t, 2H), 4.07 (s, 3H), 7.34 (d, 1H,J=8.4 Hz), 7.68 (d, 1H, J=8.7 Hz) 7.94 (d, 1H, J=8.4 Hz), 7.94 (d, 1H,J=8.7 Hz) 8.44 (s, 1H, J=2.4 Hz) 8.76 (s, 2H), 10.12 (s, 1H), 10.77 (s,1H).

EXAMPLE 6N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylcarboxamido-dibenzo[b,d]furan-1-carboxamide

IR(KBr): 3302, 2937, 1649, 1607, 1500, 1392, 1196, 1103, 809, 723 cm⁻¹.¹H NMR (300 MHz, DMSO) δ 1.10 (t, 2H), 2.34 (q, 3H), 4.07 (s, 3H), 7.33(d, 1H, J=9 Hz), 7.66 (d, 1H), 7.97-7.91 (m, 2H), 8.44 (s, 1H, J=2.4Hz), 8.75 (s, 2H), 9.95 (s, 1H), 10.72 (s, 1H).

EXAMPLE 7N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-t-butylcarboxamido-dibenzo[b,d]furan-1-carboxamide

IR (KBr): 3327, 3201, 2958, 1647, 1606, 1522, 1495, 1444, 1395, 1289,1197, 1099, 1025, 936, 806, 779, 670, 540 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ1.22 (s, 9H), 4.07 (s, 3H), 7.33 (d, 1H, J=9 Hz), 7.66 (d, 1H) 7.79 (d,1H, J=8.7 Hz), 7.93 (d, 1H, J=9 Hz), 8.51 (s, 1H, J=2.4 Hz), 8.75 (s,2H). 9.38 (s, 1H), 10.71 (s, 1H).

EXAMPLE 8N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide

IR (KBr): 3349, 3214, 2928, 1753, 1708, 1671, 1606, 1392, 1281, 1199,1183, 1022, 806, 685 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 1.33 (t, 3H), 4.08(s, 3H), 4.32 (q, 2H), 7.37 (d, 1H, J=8.4 Hz), 7.75 (d, 1H, J=8.7 Hz),7.88 (d, 1H, J=9 Hz), 7.95 (d, 1H, J=8.1 Hz), 8.69 (s, 1H, J=1.8 Hz)8.77 (s, 2H,) 10.78 (s, 1H), 10.95 (s, 1H).

EXAMPLE 9N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide

Was synthesized by hydrolysis ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide(Example 8) using potassium hydroxide (3 eq.) in methanol. mp: >250° C.

This was directly used for preparation of Example 10 with out furthercharacterisation.

EXAMPLE 10N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamidesodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide (Example 9) using 1%methanolic sodium hydroxide (1.0 eq.).

¹H NMR (300 MHz, DMSO) δ 4.08 (s, 3H), 7.32 (d, 1H, J=8.4 Hz), 7.68 (d,1H, J=8.7 Hz), 7.92 (d, 2H), 8.62 (s, 1H) 8.74 (s, 2H,) 10.19 (s, 1H),10.80 (s, 1H).

EXAMPLE 11N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(fur-2-yl-carboxamido)-dibenzo[b,d]furan-1-carboxamide

IR (KBr): 3247, 2925, 1660, 1606, 1566, 1548, 1491, 1465, 1391, 1333,1221, 1093, 1023, 890, 814, 768, 611 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 4.08(s, 3H), 6.68 (d, 1H, J=3.3 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.74 (d, 1H,J=9.0 Hz), 7.95-7.89 (m, 3H), 8.66 (s, 1H, J=1.8 Hz), 8.76 (s, 2H),10.36 (s, 1H), 10.77 (s, 1H).

EXAMPLE 12N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(cyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 0.77 (m, 4H), 1.80 (m, 1H), 4.08 (s, 3H),7.36 (d, 1H, J=8.4 Hz), 7.69 (d, 1H, J=9.0 Hz), 7.80 (m, 2H), 8.47 (d,1H, J=1.8 Hz), 8.79 (s, 2H), 10.34 (s, 1H), 10.80 (s, 1H). IR (KBr)3290, 3164, 1650, 1546, 1492, 1398, 1292, 1198, 1100, 960, 812, 640 cm⁻¹

EXAMPLE 13N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dicyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 0.98 (m, 4H), 1.14 (m, 4H), 1.82 (m, 1H),2.12 (m, 1H), 4.07 (s, 3H), 7.19 (d, 1H, J=8.7 Hz), 7.58 (d, 1H, J=8.7Hz), 7.68 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 8.79 (s, 2H), 10.40 (s, 1H).IR (KBr) 3311, 3059, 3009, 2843, 1711, 1677, 1631, 1607, 1556, 1470,1393, 1314, 1297, 1282, 1197, 1173, 1105, 1016, 810, 648 cm⁻¹

EXAMPLE 14N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoroacetamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) was treated with trifluoroacteicanhydride (57 mg, 0.27 mmol) in dichloromethane (5 ml) containingpyridine (19 mg, 0.25 mmol) at room temperature. The reaction wasstirred at room temperature for 20 h. Dichloromethane was evaporated andthe residue was triturated with cold water to obtain a white solid whichwas filtered. The solid was purified by silica gel column chromatographyusing 6% acetone-chloroform as eluent to obtain 30 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoroacetamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: >300° C.

IR (KBr): 3281, 1717, 1668, 1608, 1500, 1394, 1290, 1203, 1154, 1099,1024, 901, 809, 653 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 4.09 (s, 3H), 7.38(d, 1H, J=9 Hz), 7.80 (d, 1H), 7.89 (d, 1H, J=1.8 Hz), 7.98 (d, 1H,J=8.4 Hz), 8.67 (s, 1H, J=1.8 Hz), 8.76 (s, 2H), 10.77 (s, 1H), 11.42(s, 1H).

EXAMPLE 15N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) was treated with ethylchloroformate (40 mg, 0.374 mmol) in THF (10 ml) containing pyridine (29mg, 0.374 mmol) at 0° C. and allowed to warm to room temperature. Thereaction was stirred at room temperature for 30 min. THF was evaporatedand the residue was washed with water. The solid obtained was purifiedby silica gel column chromatography using 10% acetone-chloroform aseluent to obtain 40 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarboxamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 274° C.

IR (KBr): 3244, 3074, 2970, 2928, 1733, 1674, 1600, 1578, 1550, 1479,1391, 1278, 1236, 1210, 1102, 1062, 803 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ1.24 (t, 3H), 4.07 (s, 3H), 4.08 (q, 2H), 7.32 (d, 1H, J=8.1 Hz),7.60-7.67 (d, 2H), 7.88 (d, 1H, J=8.1 Hz), 8.45 (s, 1H), 8.76 (s, 2H),9.62 (s, 1H), 10.76 (s, 1H).

Example 16 and 17 were synthesized using reaction conditions similar toExample 15 except for using the appropriately substituted chloroformateinstead of ethyl chloroformate.

EXAMPLE 16N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isobutyloxycarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ: 0.91 (d, J=6.6 Hz, 6H), 1.84-1.96 (m, 1H),3.84 (d, J=6.9 Hz, 2H), 4.08 (s, 3H), 7.34 (d, J=8.4 Hz, 1H), 7.67 (s,2H), 7.92 (d, J=8.7 Hz, 1H), 8.48 (s, 1H), 8.79 (s, 1H), 9.69 (s, 2H),10.78 (s, 1H). IR (KBr): (cm⁻¹) 3318, 3175, 2960, 1688, 1293, 1102

EXAMPLE 17N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 4.09 (s, 3H), δ 7.12 (d, 1H, J=8.4 Hz), δ7.23-7.47 (m, 5H), δ 7.73 (d, 1H, J=9.0 Hz), δ 7.80 (d, 1H, J=8.7 Hz), δ8.02 (d, 1H, J=8.7 Hz), δ 8.31 (d, 1H, J=6.4 Hz), δ 8.97 (s, 2H), δ10.45(s, 1H). IR (KBr) 3358, 2918, 1777, 1750, 1610, 1560, 1493, 1391, 1284,1235, 1192, 1003, 803, 619 cm⁻¹

EXAMPLE 18N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopropylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide

A solution of cyclopropyl methanol (70 mg, 0.273 mmol) in THF (3 ml) wascooled to −30C. To this solution was added triethylamine (37 mg, 0.374mmol) and stirred for 10 min. A solution of triphosgene (73 mg, 0.249mmol) in THF (3 ml) was added at −30° C. to the above solution andstirred for 30 min at room temperature. This solution was then added toa suspension ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) and triethylamine (37 mg, 0.374mmol) in THF (5 ml). The reaction was stirred at room temperature for 30min. THF was evaporated and the residue was washed with water. The solidobtained was purified by silica gel column chromatography using 10%acetone-chloroform as eluent to obtain 15 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopropylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 272° C.

¹H NMR (300 MHz, DMSO-d₆) δ 0.29 (q, 2H, J=6.0 Hz), δ 0.52 (q, 2H, J=6.3Hz), δ 1.14 (m, 1H), δ 3.88 (d, 2H, J=7.2 Hz), δ 4.06 (s, 3H), δ 7.32(d, 1H, J=8.1 Hz), δ 7.60 (d, 1H, J=8.4 Hz), δ 7.66 (d, 1H, J=8.7 Hz), δ7.90 (ds, 1H, J=8.1 Hz), δ 8.48 (d, 1H, J=2.4), δ 8.76 (s, 2H), δ 9.69(s, 1H), δ 10.75 (s, 1H). IR (KBr) 2960, 2735, 1672, 1596, 1473, 1461,1323, 1271, 1180, 1113, 1089, 1001, 945, 817, 767 cm⁻¹

EXAMPLE 19N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamide

Was synthesized using reaction conditions similar to Example 17 exceptfor using the 2,2,2-trifluoroethanol instead of cyclopropylmethanol.mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 4.07 (s, 3H), 4.77 (q, 2H, J=9.0 Hz), 7.35(d, 1H, J=8.4 Hz), 7.63 (d, 1H, J=9.3 Hz), 7.72 (d, 1H, J=9.0 Hz), 7.93(d, 1H, J=8.4 Hz), 8.52 (s, 1H), 8.76 (s, 2H), 10.18 (brs, 1H), 10.76(s, 1H). IR (KBr) 3342, 2921, 1670, 1640, 1547, 1482, 1389, 1284, 1256,1184, 954, 810, 758, cm⁻¹

EXAMPLE 20N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-N,N-diethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

Step 1:N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(400 mg, 0.99 mmol) (intermediate 1) was treated with phenylchloroformate (190 mg, 1.09 mmol) in THF (15 ml) containing pyridine(0.5 ml) at 0° C. and allowed to warm to room temperature. The reactionwas stirred at room temperature for 12 h. THF was evaporated and theresidue was washed with water and hot ethanol to obtain 400 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamideas white solid which was used as such in the next step.

Step 2:N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-N,N-diethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamide(from step 1) (100 mg, 0.19 mmol), was dissolved in DMSO (2.0 ml) and asolution of N,N-diethylamine (20 mg, 0.28 mmol) in DMSO (1.0 ml) wasadded slowly to the above solution. The reaction mixture was stirred at50° C. for 5 h, cooled to room temperature and diluted with ice water(25 ml). The solid that separated as a result was filtered, dried andpurified by silica gel column chromatography using 10% methanol inchloroform as eluent to obtain 45 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-N,N-diethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (t, 6H, J=7.2 Hz), δ 3.25 (q, 4H, J=5.1Hz), δ 4.06 (s, 3H), δ 7.31 (d, 1H, J=8.4 Hz), δ 7.59 (s, 2H), δ 7.90(d, 1H, J=8.4 Hz), δ 8.32 (s, 1H), δ 8.75 (s, 2H), δ 10.74 (s, 1H). IR(KBr) 3357, 2932, 1673, 1631, 1552, 1474, 1396, 1285, 1198, 1101, 952,805, 670, cm−1

Example 21, 22, 24, 25, 26, 27, 28 and 29 were synthesized usingreaction conditions similar to step 2 of Example 21 except for using theappropriate primary or secondary amine instead of N,N-diethylamine.

EXAMPLE 21N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopentylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO) δ 1.355 (m, 2H), 1.57 (m, 4H), 1.81 (m, 2H) 3.94(m, 1H), 4.07 (s, 3H), 6.03 (d, 1H), 7.34 (d, 1H), 7.63 (d, 1H), 7.96(m, 2H), 8.11 (1H), 8.43 (s, 1H), 8.79 (s, 2H), 10.8 (s, 1H) IR (KBr):3311, 3142, 2957, 1658, 1633, 1564, 1491, 1477, 1295, 1223, 1198, 1101,1025, 806 cm⁻¹.

Mass: (M+H)=513.3

EXAMPLE 22N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 2.23 (s, 3H), 2.50 (brm, 4H), 3.43 (brm,4H), 4.08 (s, 3H), 7.34 (d, 1H, J=8.7 Hz), 7.63 (s, 2H), 7.95 (d, 1H,J=8.4 Hz), 8.35 (s, 1H), 8.68 (s, 1H), 8.78 (s, 2H), 10.77 (s, 1H). IR(KBr) 3358, 2919, 1667, 1635, 1556, 1593, 1479, 1397, 1285, 1241, 1106,1002, 802, 619 cm⁻¹

EXAMPLE 23N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide hydrochloride

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-ylcarboxamido-dibenzo[b,d]furan-1-carboxamide using methanolicHCl.mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.77 (d, 3H, J=4.2 Hz), 3.02 (m, 2H),3.24-3.43 (brm, 4H), 4.08 (s, 3H), 4.23 (m, 2H), 7.34 (d, 1H, J=8.7 Hz),7.63 (s, 2H), 7.89 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 9.03 (s, 1H), 10.63(s, 2H), 11.23 (s, 1H).

EXAMPLE 24N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(4-hydroxypiperidin-1-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (m, 2H), 1.73 (m, 2H), 3.02 (m, 2H),3.64 (m, 1H), 3.64 (m, 2H), 4.08 (s, 3H), 4.75 (brs, 1H), 7.34 (d, 1H,J=8.7 Hz), 7.63 (s, 2H), 7.94 (d, 1H, J=8.4 Hz), 8.35 (s, 1H), 8.64 (s,1H), 8.78 (s, 2H), 10.77 (s, 1H). IR (KBr) 3349, 2912, 1662, 1636, 1561,1596, 1480, 1391, 1285, 1244, 1113, 1005, 811, 621 cm⁻¹

EXAMPLE 25 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(morphol-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 3.40 (t, 4H, J=5.1 Hz), δ 3.58 (t, 4H, J=5.1Hz), δ 4.06 (s, 3H), δ 7.32 (d, 1H, J=8.4 Hz), δ 7.61 (s, 2H), δ 7.93(d, 1H, J=8.4 Hz), δ 8.33 (s, 1H), δ 8.66 (s, 1H), δ 8.75 (s, 2H), δ10.75 (s, 1H). IR (KBr) 3345, 2911, 2782, 1665, 1642, 1551, 1479, 1397,1278, 1251, 1187, 1026, 945, 810, 761 cm⁻¹.

EXAMPLE 26 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isopropylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (d, 3H, J=6.6 Hz), 1.23 (m, 1H), 1.31(d, 2H, J=6.6 Hz), 4.07 (s, 3H), 7.33 (d, 1H, J=8.7 Hz), 7.38 (d, 1H,J=7.8 Hz), 7.66 (d, 1H, J=9.3 Hz), 7.72 (dd, 1H, J=9.3 Hz and J=2.1 Hz),7.91 (d, 1H, J=8.4 Hz), 8.39 (d, 1H, J=2.1 Hz), 8.75 (s, 2H), 9.68 (s,1H), 10.77 (s, 1H). IR (KBr) 3354, 2927, 1668, 1638, 1552, 1491, 1396,1280, 1251, 1196, 951, 802, 761, cm⁻1

EXAMPLE 27 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-n-hexylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, 3H), 1.23 (m, 8H), 3.1 (q, 2H),4.06 (s, 3H), 5.96 (t, 1H), 7.30 (d, 1H, J=8.7 Hz), 7.60 (d, 1H, J=9.0Hz), 7.90 (m, 2H), 8.10 (s, 1H), 8.53 (s, 1H), 8.75 (s, 2H), 10.76 (s,1H). IR (KBr) 3360, 2938, 1667, 1634, 1582, 1478, 1398, 1284, 1241,1196, 953, 803, 671, cm⁻¹

EXAMPLE 28 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ: 1.03 (t, J=7.2 Hz, 3H), 3.07-3.12 (q, 2H),4.07 (s, 3H), 5.96 (t, J=6 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.62 (d, J=9Hz, 1H), 7.92 (dd, J=3.3 Hz, 8.7 Hz, 2H), 8.14 (d, J=2.1 Hz, 1H), 8.59(s, 1H), 8.79 (s, 1H), 10.81 (s, 2H) IR (KBr): 3322, 3146, 1657, 1637,1294, 1101 cm⁻¹

EXAMPLE 29 N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ: 2.63 (d, J=4.8 Hz, 3H), 4.07 (s, 3H),5.86-5.89 (m, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.62 (d, J=9 Hz, 1H), 7.92(d, J=8.7 Hz, 2H), 8.16 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 8.79 (s, 1H),10.81 (s, 2H) IR (KBr): 3337, 3149, 1659, 1637, 1295, 1098 cm⁻¹

EXAMPLE 30N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(70 mg, 0.159 mmol) (intermediate 2) was treated with methanesulfonylchloride (22 mg, 0.194 mol) in THF (10 ml) containing pyridine (0.5 ml)at 0° C. and allowed to warm to room temperature. The reaction wasstirred at room temperature for 2 h. THF was evaporated and the residuewas washed with saturated sodium bicarbonate solution, water. The solidobtained was purified by silica gel column chromatography using 12%acetone-chloroform as eluent to obtain 37 mg ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonylamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.95 (s, 3H), 7.5 (dd, 1H, J=8.7 Hz andJ=2.4 Hz), 7.58 (t, 1H, J=72 Hz), 7.6 (d, 1H, J=8.4 Hz), 7.85 (d, 1H,J=9.3 Hz), 7.93 (d, 1H, J=8.1 Hz), 8.30 (d, 1H, J=2.4 Hz), 8.82 (s, 2H),9.77 (s, 1H), 11.06 (s, 1H). IR (KBr) 3323, 2926, 1698, 1636, 1489,1396, 1283, 1266, 1142, 1040, 812, 621 cm⁻¹

EXAMPLE 30a

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideN-oxide

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methansulfonamido-dibenzo[b,d]furan-1-carboxamideN-oxide (Example 30a) was prepared by the procedure described in Example47, except the starting material used wasN-(3,5-dichloropyrid-4-yl)-4-difluoromethyxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide(Example 30) instead ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide(Example 4). ¹H NMR (300 Mhz, DMSO-d₆) δ: 2.94 (s, 3H), 7.51 (d, 1H),7.58 (t, 1H J=72 Hz), 7.62 (d, 1H), 7.85 (d, 1H), 7.90 (d, 1H), 8.28 (s,1H), 8.79 (s, 2H), 9.79 (s, 1H), 10.89 (s, 1H).

EXAMPLE 31N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidesodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide(Example 30) using 1% methanolic sodium hydroxide (1.0 eq.).

¹H NMR (300 MHz, DMSO-d₆) δ 2.95 (s, 3H), 7.26 (d, 2H, J=8.7 Hz), 7.40(t, 1H, J=72 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.95 (d, 1H, J=9.3 Hz), 8.19(s, 2H), 8.68 (brs, 1H), 9.66 (brs, 1H). IR (KBr) 2920, 1651, 1524,1463, 1391, 1278, 1194, 1105, 1005, 882, 815 cm⁻¹

Example 32 and 33 were synthesized using reaction conditions similar toExample 30 except for using the appropriate substituted sulfonylchloride instead of methane sulfonyl chloride.

EXAMPLE 32N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethanesulfonamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 3H, J=7.2 Hz), 3.03 (q, 2H, J=7.2Hz), 7.49 (dd, 1H, J=8.7 Hz and J=2.1 Hz), 7.58 (t, 1H, J=73 Hz), 7.81(d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=8.7 Hz), 8.29 (d, 1H, J=2.4 Hz) 8.82(s, 2H), 9.85 (s, 1H), 11.06 (s, 1H). IR (KBr): 3264, 2988, 1672, 1590,1562, 1472, 1256, 1192, 1134, 1028, 973, 733 cm⁻¹

EXAMPLE 33N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-N,N-dimethylaminosulfonamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 2.7 (s, 6H), 7.49 (dd, 1H, J=8.7 Hz andJ=2.1 Hz), 7.57 (t, 1H, J=73 Hz), 7.59 (d, 1H, J=8.4 Hz), 7.81 (d, 1H,J=8.7 Hz), 7.92 (d, 1H, J=8.4 Hz), 8.28 (s, 2H), 9.93 (s, 1H), 11.05 (s,1H). IR (KBr) 3274, 3012, 1660, 1602, 1579, 1483, 1279, 1200, 1121,1009, 823, 623 cm⁻¹

EXAMPLE 34N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(70 mg, 0.159 mmol) (intermediate 2) was treated with acetyl chloride(22 mg, 0.299 mmol) in THF (10 ml) containing pyridine (0.5 ml) at 0° C.and allowed to warm to room temperature. The reaction was stirred atroom temperature for 2.0 h. THF was evaporated and the residue waswashed with saturated sodium bicarbonate solution 5% HCl and water. Thesolid obtained was purified by silica gel column chromatography using10% acetone-chloroform as eluent to obtain 25 mg ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 234° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (s, 3H), 7.4 (d, 1H, J=8.4 Hz), 7.53(t, 1H, J=73 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.77-7.86 (m, 3H), 8.36 (d,1H, J=2.4 Hz), 8.81 (s, 2H), 10.25 (s, 1H). IR (KBr) 3344, 2924, 1727,1712, 1686, 1555, 1390, 1367, 1288, 1269, 1116, 1047, 822, 584 cm⁻¹

Example 35, 36, 37, and 40 were synthesized using reaction conditionssimilar to Example 34 except for using the appropriate substituted acidchloride instead of acetyl chloride

EXAMPLE 35N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(1-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 2.12 (m, 2H), 2.61 (t, 2H, J=7.2 Hz), 3.75(t, 2H, J=6.9 Hz), 7.61 (d, 1H, J=7.8 Hz), 7.63 (t, 1H, J=73 Hz), 7.79(d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.4 Hz), 8.18 (dd, 1H, J=9.3 Hz andJ=2.4 Hz), 8.65 (d, 1H, J=2.2 Hz) 8.82 (s, 2H), 10.35 (s, 1H). IR (KBr)3281, 3156, 2987, 1664, 1650, 1526, 1496, 1381, 1284, 1217, 1146, 1110,814, 677 cm⁻¹.

EXAMPLE 36N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-cyclopropylcarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (m, 2H), 1.23 (m, 2H), 1.80 (m, 1H),7.60 (d, 1H, J=8.4 Hz), 7.58 (t, 1H, J=73 Hz), 7.76 (d, 1H, J=8.4 Hz),7.94 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=8.4 Hz), 8.44 (s, 1H), 8.81 (s,2H), 10.40 (s, 1H), 11.02 (s, 1H). IR (KBr) 3289, 3143, 1660, 1650,1528, 1494, 1400, 1279, 1195, 1150, 1106, 1056, 819 cm⁻¹.

EXAMPLE 37N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 1.33 (t, 3H), 4.32 (q, 2H), 7.57 (t, 1H,J=72 Hz), 7.62 (d, 1H, J=8.7 Hz), 7.84 (d, 1H, J=8.7 Hz), 7.86-7.96 (m,2H), 8.69 (d, 1H, J=1.8 Hz) 8.81 (s, 2H,) 11.04 (s, 2H). IR (KBr) 3206,3107, 2987, 1759, 1702, 1669, 1548, 1499, 1384, 1296, 1279, 1222, 1191,1118, 1055, 810 cm⁻¹.

EXAMPLE 38N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide

Was synthesized by hydrolysis ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide(Example 37) using potassium hydroxide (3 eq.) in methanol.

¹H NMR (300 MHz, DMSO-d₆) δ 7.58 (t, 1H, J=72 Hz), 7.62 (d, 1H, J=8.4Hz), 7.86 (d, 1H, J=8.7 Hz), 7.91-7.96 (m, 2H), 8.76 (d, 1H, J=1.8 Hz)8.81 (s, 2H,) 10.97 (s, 1H), 11.04 (s, 1H).

EXAMPLE 39N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamidedisodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamide(Example 38) using ethanolic sodium ethoxide (2.0 eq.).

¹H NMR (300 MHz, DMSO-d₆) δ 7.30 (d, 1H, J=8.7 Hz), 7.42 (t, 1H, J=72Hz), 7.65 (d, 1H, J=8.7 Hz), 7.98 (d, 1H, J=8.7 Hz), 8.06 (dd, 1H, J=9.0and 1.8 Hz) 8.21 (s, 2H) 9.08 (d, 1H, J=2.4 Hz), 10.08 (s, 1H).

EXAMPLE 40N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 6.68 (d, 1H, J=3.3 Hz), 7.35 (d, 1H, J=3.3Hz), 7.59 (t, 1H, J=72 Hz), 7.62 (d, 1H, J=8.4 Hz), 7.82 (d, 1H, J=9.0Hz), 7.93-7.99 (m, 3H), 8.66 (s, 1H, J=1.8 Hz), 8.81 (s, 2H), 10.44 (s,1H), 11.04 (s, 1H) IR (KBr) 3288, 3031, 1651, 1586, 1556, 1518, 1498,1386, 1281, 1193, 1117, 1046, 809, 750 cm⁻¹.

EXAMPLE 41N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

Step 1: N1-phenyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid chloride (200 mg,0.696 mmol) (from step 5a of intermediate 1) was reacted with aniline(2.0 eq.) in THF (10 ml) in the presence of diisopropylethylamine (3eq.) at room temperature for 16 h. The yellow suspension was filteredand the solid obtained was washed with 5% HCl and water to obtain 110 mgof N1-phenyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide as whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 4.15 (s, 3H), 7.18 (t, 1H), 7.43 (m, 3H),7.80 (d, 2H), 7.95 (d, 1H), 8.01 (d, 1H), 8.45 (d, 1H), 9.40 (s, 1H),10.60 (s, 1H).

Step 2: N1-phenyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

N1-phenyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (100 mg)(from step 1) was reduced using raney nickel (100 mg) in methanol (40ml) and DMF (10 ml) in the presence of hydrazine hydrate (0.5 ml) undergentle reflux for 1 h. The reaction mixture was fliterd through celiteand the filterate was concentrated in vaccuo. The residue was trituratedwith water, to obtain a solid which was filtered dried to give theproduct as white solid (90 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.15 (s, 3H), 5.03 (brs, 2H), 6.80 (d, 1H),7.08 (t, 1H), 7.11 (d, 1H), 7.40 (m, 4H), 7.60 (d, 1H), 7.93 (d, 2H),10.43 (s, 1H).

Step 3: N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N1-phenyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (69 mg,0.207 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF(10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm toroom temperature. The reaction was stirred at room temperature for 2 h.THF was evaporated and the residue was washed ethanol to obtain 40 mg ofN1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as whitesolid; mp: 252° C.

IR (KBr): 3316, 3237, 2937, 1650, 1531, 1596, 1507, 1472, 1439, 1292,1195, 187, 1100, 809, 753 cm⁻¹. ¹H NMR (300 MHz, DMSO) δ 2.03 (s, 3H),4.05 (s, 3H), 7.14 (t, 1H), 7.28 (d, 1H), 7.39 (t, 2H), 7.66-7.74 (m,2H), 7.82 (d, 2H), 7.91 (dd, 1H, J=9.0 and 2.7 Hz), 8.37 (d, 1H, J=2.4Hz), 10.10 (s, 1H), 10.50 (s, 1H).

EXAMPLE 42N1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

Step 1:N1-(4-methoxyphenyl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid chloride (200 mg,0.696 mmol) (from step 5a of intermediate 1) was reacted with 4-methoxyaniline (2.0 eq.) in THF (10 ml) in the presence ofdiisopropylethylamine (3 eq.) at room temperature for 16 h. The yellowsuspension was filtered and the solid obtained was washed with 5% HCland water to obtain 153 mg ofN1-(4-methoxyphenyl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamideas white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 3.90 (s, 3H), 4.15 (s, 3H), 6.99 (d, 2H),7.42 (d, 1H), 7.77 (d, 2H), 7.96 (d, 1H), 8.02 (d, 1H), 8.43 (d, 1H),9.40 (s, 1H), 10.60 (s, 1H).

Step 2:N1-(4-methoxyphenyl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

N1-(4-methoxyphenyl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide(140 mg) (from step 1) was reduced using raney nickel (100 mg) inmethanol (40 ml) and DMF (10 ml) in the presence of hydrazine hydrate(1.0 ml) under gentle reflux for 1 h. The reaction mixture was fliterdthrough celite and the filterate was concentrated in vaccuo. The residuewas triturated with water, to obtain a solid which was filtered dried togive the product as white solid (90 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (s, 3H), 4.05 (s, 3H), 5.03 (brs, 2H),6.90 (d, 1H), 7.01 (d, 2H), 7.20 (d, 1H), 7.40 (m, 2H), 7.60 (d, 1H),7.88 (d, 2H), 10.43 (s, 1H).

Step 3:1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N1-(4-methoxyphenyl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(90 mg, 0.248 mmol) (step 2) was treated with acetyl chloride (1.1 eq.)in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warmto room temperature. The reaction was stirred at room temperature for 16h. THF was evaporated and the residue was washed ethanol to obtain 40 mgofN1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 285° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.03 (s, 3H), 3.77 (s, 3H), 4.05 (s, 3H),6.96 (d, 2H), 7.27 (d, 1H), 7.65-7.74 (m, 4H), 7.91 (dd, 1H, J=9.0 and2.7 Hz), 8.37 (d, 1H, J=2.4 Hz), 10.10 (s, 1H), 10.36 (s, 1H). IR (KBr)3256, 2938, 2839, 1645, 1599, 1531, 1514, 1469, 1412, 1291, 1195, 1178,1099, 1023, 825, 812 cm⁻¹.

EXAMPLE 43N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

Step 1: N1-benzyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid chloride (200 mg,0.696 mmol) (from step 5a of intermediate 1) was reacted withbenzylamine (2.0 eq.) in THF (10 ml) in the presence ofdiisopropylethylamine (3.0 eq.) at room temperature for 16 h. Thesuspension was filtered and the solid obtained was washed with 5% HCland water to obtain 170 mg ofN1-benzyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide as whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 4.08 (s, 3H), 4.62 (d, 2H), 7.15 (d, 1H),7.18-7.23 (m, 5H), 7.84 (d, 1H), 8.01 (d, 1H), 8.42 (dd, J=8.4 and 2.4Hz), 9.14 (brt, 1H), 9.58 (d, 1H, J=2.4 Hz)

Step 2: N1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

N1-benzyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (125 mg,0.33 mmol) (from step 1) and iron powder (56 mg, 1.0 mmol) was suspendedin 50% aqueous ethanol (10 ml) and reflux for 10 min. To this was addeda solution of concentrated HCl (7 ul in 5 ml 50% aqueous ethanol) andrefluxed for 4 h. The reaction mixture was flitered hot through celiteand the filterate was basified with 15% ethanolic KOH, filtered and thefilterate was concentrated in vaccuo. The residue was triturated withwater, to obtain a solid which-was filtered dried to give the product aswhite solid (90 mg) mp: 228° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.99 (s, 3H), 4.57 (d, 2H), 4.97 (brs, 2H),6.80 (dd, 1H), 7.12 (d, 1H), 7.29 (d, 1H), 7.34-7.42 (m, 5H), 7.51-7.59(m, 2H), 9.01 (t, 1H).

Step 3: N1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N-1-benzyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (80 mg,0.23 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF(10 ml) containing pyridine (1.0 eq) at 0° C. and allowed to warm toroom temperature. The reaction was stirred at room temperature for 2 h.The reaction mixture was filterd and the filterarte was concentrated.The residue was triturated with ethanol to obtain 63 mg ofN1-benzyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as whitesolid; mp: 264-265° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.07 (s, 3H), 4.03 (s, 3H), 4.58 (d, 2H),7.21-7.27 (m, 2H), 7.33-7.43 (m, 4H), 7.64 (d, 2H), 7.87 (dd, 1H, J=8.7and 2.7 Hz), 8.54 (d, 1H, J=2.7 Hz), 9.09 (t, 1H), 10.14 (s, 1H). IR(KBr) 3313, 3261, 3035, 2925, 2844, 1660, 1637, 1626, 1530, 1506, 1287,1227, 1192, 1103, 1025, 810, 741, 696 cm⁻¹.

EXAMPLE 44N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide(100 mg, 0.249 mmol) (intermediate 1) was suspended in THF (2 ml)followed by addition of pyridine (29 mg, 0.37 mmol) at room temperature.Reaction mixture was stirred for 10 min. followed addition of solutionethyl isothiocyanate (32 mg, 0.374 mmol) in THF (2 ml). The reactionmixture was stirred at room temperature for 3-4 days. THF was evaporatedand the residue was stirred in water (5 ml). After filteration, thesolid obtained was purified by silica gel column chromatography using15% acetone-chloroform as eluent to obtain 40 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamideas white solid; mp: 260° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (t, 3H), 3.24 (q, 2H), 4.14 (s, 3H),7.34 (d, 1H, J=8.4 Hz), 7.59 (m, 3H), 7.70 (d, 1H, J=8.1 Hz), 7.89 (d,1H, J=8.1 Hz), 8.32 (s, 1H), 8.76 (s, 2H), 9.45 (s, 1H), 10.79 (s, 1H).IR (KBr) 3434, 3200, 3049, 2928, 1656, 1606, 1553, 1493, 1394, 1286,1257, 1099, 803 cm⁻¹

EXAMPLE 45N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(n-butylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆)) δ 0.92 (t, 3H), 1.24 (m, 2H), 1.54 (m, 2H),3.34 (m, 2H) 4.14 (s, 3H), 7.34 (d, 1H, J=8.4 Hz), 7.65 (m, 2H), 7.91(d, 1H, J=8.1 Hz), 8.24 (s, 1H), 8.32 (s, 1H), 8.75 (s, 2H), 9.44 (s,1H), 10.75 (s, 1H). IR (KBr)3195, 2928, 1658, 1606, 1549, 1480, 1393,1283, 1257, 1194, 1100, 1021, 807 cm⁻¹

EXAMPLE 46N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

Step 1:N1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide

4-methoxy-8-nitro dibenzo[b,d]furan-1-carboxylic acid chloride (600 mg,1.92 mmol) (from step 5a of intermediate 1) was reacted with3-aminopyridine (1.1 eq.) in THF (20 ml) in the presence ofdiisopropylethylamine (0.5 ml) at room temperature for 12 h. Thesuspension was filtered and the solid obtained was washed with 5% HCland water to obtain 500 mg ofN1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide aswhite solid.

¹H NMR (300 MHz, DMSO-d₆) δ 4.15 (s, 3H), 7.44 (m, 2H), 8.00 (m, 2H),8.26 (d, 1H, J=7.5 Hz), 8.35 (d, 1H, J=4.5 Hz), 8.46 (dd, 1H, J=9.0, 2.7Hz), 8.95 (s, 1H), 9.37 (d, 1H, J=2.7 Hz), 10.77 (s, 1H).

Step 2:N1-(pyrid-3-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide

N1-(pyrid-3-yl)-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (500mg) (from step 1) was reduced using raney nickel (150 mg) (30% w/waqueous suspension) in methanol (10 ml) in the presence of hydrazinehydrate (0.32 ml) under gentle reflux for 4 h. The reaction mixture wasflitered through celite and the filterate was concentrated in vaccuo.The residue was triturated with water, to obtain a solid which wasfiltered dried to give the product as white solid (300 mg).

Step 3:N1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

N1-(pyrid-3-yl)-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (100mg, 0.30 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) inTHF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm toroom temperature. The reaction was stirred at room temperature for 1 h.THF was evaporated and the residue was purified by silica gel columnchromatography using 25% acetone-chloroform as eluent to obtain 6 mg ofN1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide aswhite solid; mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆) δ: 2.04 (s, 3H), 4.07 (s, 3H), 7.31 (d, 1H,J=8.1 Hz), 7.43-7.47 (dd, 1H J=8.2, 4.8 Hz), 7.68 (d, 1H, J=8.7 Hz),7.78 (d, 1H, J=8.4 Hz), 7.90 (dd, 1H, J=2.4 Hz, 9 Hz), 8.22-8.25 (d,1H), 8.35 (d, 1H, J=3.9 Hz), 8.41 (d, 1H, J=2.4 Hz), 8.98 (s, 1H), 10.10(s, 1H), 10.71 (s, 1H) IR (KBr): (cm⁻¹) 3271, 2922, 1646, 1289, 1102,803.

EXAMPLE 47N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-N-oxide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide(0.215 gm, 0.49 mmole) (Example 4) was suspended in dichloromethane. Tothis reaction mixture was added 0.507 gm (2.9 mmoles) ofmeta-chloroperbenzoic acid (50%) and reaction mixture was refluxed for 3hours and stirred at room temp. for 12 hours. Dichloromethane wasremoved under vaccum and the crude compound was purified through silicagel column to obtain 0.066 gm (30%) of the N-oxide.

¹H NMR (300 MHz, DMSO-d₆) δ: 2.01 (s, 3H), 4.06 (s, 3H), 7.33 (d, 1H),7.67 (d, 1H), 7.90 (m, 2H), 8.43 (d, 1H), 8.75 (s, 2H), 10.07 (s, 1H),10.61 (s, 1H) IR (KBr): 3308, 3118, 2926, 2853, 1656, 1606, 1542, 1489,1285, 1102, 828 cm⁻¹

Mass: (M+H)=460.1

EXAMPLE 48N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxide

Was synthesized by using reaction conditions similar to those for thepreparation of Example 47 except for starting withN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide(0.2 gm, 4 mmoles) (Example 1) instead ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide(Example 4).

Yield=0.04 gm (19%). ¹H NMR (300 MHz, DMSO-d₆) δ: 2.93 (s, 3H), 4.082(s, 3H), 7.373 (d, 1H), 7.44 (d, 1H), 7.77 (d, 1H IR (KBr): −526, 3304,2926, 2851, 1654, 1606, 1484, 1279, 1235, 1150, 1103, 987, 828 cm⁻¹

Mass: −(M+H)=496.1

EXAMPLE 49N-(pyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide

A solution ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide(60 mg) (Example 4) and 25-28% aqueous ammonium hydroxide (3 ml) in THF(35 ml) was hydrogenated at 50 psi using 10% Pd/C (60 mg) for 24 h atroom temperature. The reaction was filtered through celite and thefiltrate was concentrated. The residue was dissolved in DCM, washed withwater and brine, dried over anhydrous sodium sulfate and concentrated.The residue was purified by silica gel column chromatography using 2-10%methanol in DCM as eluent to obtain 21 mg (42%) ofN-(pyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide aswhite solid. mp: 267-268° C.

¹H NMR (300 MHz, DMSO-d₆) δ: 2.04 (s, 3H), 4.07 (s, 3H), 7.30 (d, 2H,J=8.7 Hz), 7.68 (d, 1H, J=8.7 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.82 (d, 2H,J=6.6 Hz), 7.88 (dd, 1H, J=1.8 and 8.7 Hz), 8.40 (d, 1H, J=1.8 Hz), 8.52(d, 2H, J=6.0 Hz), 10.11 (s, 1H), 10.88 (s, 1H). IR (KBr): 3243, 3140,2976, 2931, 2844, 1696, 1669, 1633, 1599, 1579, 1509, 1473, 1385, 1330,1285, 1269, 1202, 1102, 827, 808 cm⁻¹

EXAMPLE 50N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamide(Example 17) (100 mg, 0.19 mmol), was dissolved in DMSO (2.0 ml) and asolution of glycine ethyl ester hydrochloride (26 mg, 0.19 mmol) andtriethylamine (1.0 ml) in DMSO (2.0 ml) was added slowly to the abovesolution. The reaction mixture was stirred at 50° C. for 5 h, cooled toroom temperature and diluted with ice water (25 ml) and acidified with5% hydrochloric acid. The solid that separated as a result was filtered,dried and purified by silica gel column chromatography using 5% methanolin chloroform as eluent to obtain 30 mg ofN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamideas white solid; mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆)-δ: 1.19 (t, 3H), 3.87 (d, 2H), 4.08-4.14 (m,5H), 6.33 (t, 1H), 7.35 (d, 1H, J=8.7 Hz), 7.65 (d, 1H, J=9.3 Hz),7.90-7.94 (m, 2H), 8.19 (d, 1H, J=2.1 Hz), 8.79 (s, 2H), 8.98 (s, 1H),10.80 (s, 1H) IR (KBr) 3339, 3148, 2959, 1763, 1659, 1640, 1579, 1489,1392, 1292, 1199, 1159, 1100, 1022, 910, 806 cm⁻¹

EXAMPLE 51N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamide (Example 50) (150 mg,0.28 mmol) was hydrolysed using potassium hydroxide (2 eq.) in 3 mlwater and 3 ml methanol for 30 min. at room temperature. The solidprecipitated was filtered and washed with methanol to obtain the productas white solid (50 mg). mp: >250° C.

¹H NMR (300 MHz, DMSO-d₆)-δ: 3.80 (d, 2H), 4.08 (s, 3H), 6.28 (t, 1H),7.33 (d, 1H, J=8.7 Hz), 7.64 (d, 1H, J=9.3 Hz), 7.93 (m, 2H), 8.18 (d,1H, J=2.1 Hz), 8.79 (s, 2H), 8.97 (s, 1H), 10.80 (s, 1H), 12.5 (brs,1H). IR (KBr) 3322, 3138, 2936, 1740, 1657, 1638, 1567, 1522, 1394,1293, 1218, 1198, 1098, 1024, 910, 886, 806, 721 cm⁻¹

EXAMPLE 52N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-aminodibenzo[b,d]furan-1-carboxamide (500 mg, 1.24 mmol) was suspended inethanol and a 50% solution of ethyl glyoxalate in toluene (384 mg, 3.72mmol) was added to the suspension. The reaction mixture was hydrogenatedat 40 psi in presence of pre-activated raney nickel (50% w/w) for 24h-48 h. The reaction was filtered and the filterate was concentrated invacuo. The residue was purified by silica gel (100-200) columnchromatography using 0.5% methanol in dichloromethane to obtain thecompound as a pale yellow solid (180 mg). mp: >270° C.

¹H NMR (300 MHz, DMSO-d₆) δ: 1.06 (t, 3H), 3.85 (d, 2H), 4.01-4.05 (m,5H), 6.09 (t, 1H), 6.88 (dd, 1H, J=8.7 and 3.0 Hz), 7.26 (d, 1H, J=8.7Hz), 7.43-7.55 (m, 2H), 7.81 (d, 1H, J=8.7 Hz), 8.79 (s, 2H), 10.75 (s,1H) IR (KBr): 3405, 3182, 2985, 1741, 1663, 1610, 1487, 1285, 1198,1096, 1023, 807 cm−1

EXAMPLE 53N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide

N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide(Example 52) (100 mg, 0.204 mmol) was hydrolysed using potassiumhydroxide (5 eq.) in 3 ml water and 3 ml methanol for 12 h at roomtemperature. The solid precitated was filted and washed with ethanol toobtain the product as pale yellow solid (50 mg). mp: >260° C.

¹H NMR (300 MHz, DMSO-d₆) δ: 3.77 (s, 2H), 4.05 (s, 3H), 6.88 (dd, 1H,J=9.0 and 2.1 Hz), 7.26 (d, 1H, J=9.0 Hz), 7.47-7.50 (m, 2H), 7.81 (d,1H, J=8.4 Hz), 8.79 (s, 2H), 10.77 (s, 1H) IR (KBr) 3416, 3177, 2936,1726, 1662, 1609, 1487, 1398, 1285, 1196, 1095, 802 cm⁻¹.

EXAMPLE 54N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-acetamido-9H-4-carbazolecarboxamide

N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide(75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine(28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. Thesolution obtained, was added with a solution of acetyl chloride in dryTHF (5 ml). The reaction mixture was stirred for 1 hr. THF wasevaporated and the solid was washed with water to get crude solid whichwas column chromatographed using 10% methanol in chloroform to giveN-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-acetamido-9H-4-carbazolecarboxamide(20 mg), mp>250° C.

IR (KBr): 3292, 3171, 2935, 2838, 1658, 1575, 1547, 1483, 1397, 1283,1260, 1234, 1106, 808 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.01 (s, 3H), 4.04(s, 3H), 4.15 (s, 3H), 7.15 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.7 Hz),7.62 (d, 1H, J=8.1 Hz), 7.85 (dd, 1H, J=9.0 and 2.4 Hz), 8.31 (d, 1H,J=2.1 Hz), 8.78 (s, 2H), 9.89 (s, 1H), 10.67 (s, 1H).

EXAMPLE 55N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphonamido-9H-4-carbazolecarboxamide

N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide(75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine(28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. Thesolution obtained, was added with a solution of methane sulphonylchloride (30 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixturewas stirred for 1 hr. THF was evaporated and the solid was washed withwater to get crude solid which was column chromatographed using 10%methanol in chloroform to giveN-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphon-amido-9H-4-carbazolecarboxamide(20 mg), mp>250° C.

IR (KBr): 3268, 3138, 2962, 2935, 1655, 1573, 1547, 1483, 1400, 1311,1257, 1235, 1144, 938, 804 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.50 (s, 3H),4.05 (s, 3H), 4.17 (s, 3H), 7.18 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H, J=9.0and 2.1 Hz), 7.41-7.64 (m, 2H), 8.30 (d, 1H, J=2.4 Hz), 8.79 (s, 2H),9.41 (s, 1H), 10.71 (s, 1H).

EXAMPLE 56N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethanesulphonamido-9H-4-carbazolecarboxamide

N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide(75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine(28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. Thesolution obtained, was added with a solution of ethane sulphonylchloride (34 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixturewas stirred for 1 hr. THF was evaporated and the solid was washed withwater to get crude solid which was column chromatographed using 10%methanol in chloroform to giveN-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-ethanesulphonamido-9H-4-carbazolecarboxamide (20 mg), mp>250° C.

IR (KBr): 3270, 3140, 2935, 1677, 1574, 1481, 1325, 1256, 1144, 1108,949, 732 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 1.24 (t, 3H), 2.95 (q, 2H),4.05 (s, 3H), 4.17 (s, 3H), 7.16 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H, J=9.0and 2.1 Hz), 7.58-7.63 (m, 2H), 8.29 (d, 1H, J=2.4 Hz), 8.79 (s, 2H),9.49 (s, 1H), 10.70 (s, 1H).

EXAMPLE 57N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-propionamido-9H-4-carbazolecarboxamide

N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide(75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine(28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. Thesolution obtained, was added with a solution of propionyl chloride (24mg, 0.00027) in dry THF (5 ml). The reaction mixture was stirred for 1hr. THF was evaporated and the solid was washed with water to get crudesolid which was column chromatographed using 10% methanol in chloroformto giveN-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-propionamido-9H-4-carbazolecarboxamide(20 mg), mp>250° C.

IR (KBr): 3282, 3138, 2966, 2938, 1656, 1645, 1481, 1397, 1313, 1283,1260, 1232, 1106, 1087, 802 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 1.15 (t,3H), 2.15 (q, 2H), 4.04 (s, 3H), 4.14 (s, 3H), 7.15 (d, 1H, J=8.4 Hz),7.52 (d, 1H, J=8.7 Hz), 7.62 (d, 1H, J=8.1 Hz), 7.88 (dd, 1H, J=9.0 and2.4 Hz), 8.33 (d, 1H, J=2.1 Hz), 8.77 (s, 2H), 9.82 (s, 1H), 10.66 (s,1H).

EXAMPLE 58N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidedisodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide(Example 30) using ethanolic sodium ethoxide

¹H NMR (300 MHz, DMSO-d₆) δ 2.53 (s, 3H), 7.06 (dd, 1H, J=8.7 and 2.1Hz), 7.14 (d, 1H, J=8.4 Hz), 7.29 (d, 1H, J=8.7 Hz), 7.37 (t, 1H, J=72Hz), 7.85 (d, 1H, J=8.4 Hz), 8.18 (s, 2H), 8.22 (d, 1H, J=2.4 Hz), IR(KBr) 2929, 1524, 1462, 1395, 1275, 1197, 1105, 1005, 890, 814 cm⁻¹

EXAMPLE 59N-(3,5-dichloropyrid-4-yl)-1-methoxy-6-acetamido-dibenzo[b,d]thiophene-4-carboxamide

Step 1: 3-nitro-4-(2-methoxy thiophenoxy)-acetophenone

To a stirred suspension of potassium fluoride (2.48 gm, 0.04286 mol) indry DMSO (10 ml) was added a solution of 2-methoxy thiophenol (5 gm,0.0357 mol) in DMSO (10 ml). A solution of 4-fluoro 3-nitro acetophenone(7.88 gm, 0.04286 mol) in DMSO (10 ml) was added to the above suspensionand the reaction mixture was stirred at 70-80° C. under nitrogen for 4h. The reaction mixture was cooled to room temperature and the contentswere poured into water (150 ml) and stirred for 15 minutes. The paleyellow coloured solid appeared was then filtered and washed withsaturated sodium bicarbonate solution followed by water and dried undervaccum. The compound was obtained as pale yellow solid (8.1 gm)mp:−136-138° C.

IR (KBr): 3374, 3095, 3054, 2920, 1958, 1831, 1694, 1611, 1538, 1351,1262, 1104, 978, 853, 814, 724 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.59 (s,3H), 3.75 (s, 3H), 6.86 (d, 1H, J=8.7 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.26(d, 1H, J=8.4 Hz), 7.65 (m, 2H), 8.05 (d, 1H, J=8.7 Hz), 8.68 (s, 1H).

Step 2: 3-amino-4-(2-methoxy thiophenoxy)-acetophenone

To the solution of 3-nitro-4-(2-methoxy thiophenoxy)-acetophenone (8 gm,0.02631 mol) in methanol, raney nickel (50%) was added. Then 4-5 kg/cm²hydrogen pressure was applied for 7 hrs at room temperature. Thereaction mixture was filtered through cilites to remove raney nickel.Filtrate was concentrated. Thick oil obtained (5.12) was used in thenext step.

IR (KBr): 2958, 2922, 2852, 1682, 1557, 1465, 1420, 1261, 1092, 1021,803, 757 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.50 (s, 3H), 3.85 (s, 3H),5.55 (s, 2 H) 6.65 (d, 1H, J=7.8 Hz), 6.84 (t, 1H, J=7.2), 7.03 (d, 1H,J=8.4 Hz), 7.19 (m, 2H), 7.29 (d, 1H, J=7.8), 8.37 (s, 1H).

Step 3: 1-methoxy-6-acetyl dibenzo[b,d]thiophene

3-amino-4-(2-methoxy thiophenoxy)-acetophenone (5 gm, 0.01824 mol) wasdissolved in 1:1 HCl (50 ml). The reaction mixture was cooled below 5°C. To this reaction mixture, sodium nitrite (1.88 gm, 0.02736 mol) wasadded slowly with maintaining temperature below 5° C. after addition,reaction was stirred for 30 minutes below 5° C. Then sodium fluoroborate(3.97 gm, 0.03648 mol) was added to it and stirred for another 30minutes at and below 5° C. Above diazotized solution was then added tothe stirred solution of copper(I) oxide (5.21 gm, 0.03648 mol) in 0.1Nsulfuric acid (1800 ml) at 35-40° C. The reaction mixture was stirredfor 15-30 minutes. Ethyl acetate was added to the reaction mixture andfiltered to remove inorganic compound. Filtrate was then extracted byethyl acetate (3×150 ml). Organic volume was washed with water followedby brine and then concentrated under vacuum. Brown colored solid (3.6gm) was obtained. mp −136-138° C.

IR (KBr): 3432, 2943, 2841, 1673, 1572, 1488, 1429, 1362, 1269, 1051,888, 822, 782 cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.73 (s, 3H), 4.02 (s,3H), 7.19 (d, 1H, J=7.8 Hz), 7.56 (t, 1H, J=7.8 Hz), 8.06 (d, 1H,J=8.7), 8.16 (m, 2H), 8.94 (s, 1H).

Step 4: Oxime Preparation

1-methoxy-6-acetyl dibenzo[b,d]thiophene (3.5 gm, 0.01286 mol) wassuspended in methanol (30 ml) to which hydroxyl amine hydrochloride(1.78 gm, 0.02573 mol), sodium hydroxide (1.029 gm, 0.02573 mol) andwater was added. Whole reaction mixture was then refluxed for 6-7 hrs.Methanol was then distilled out under vacuum. Then water was added tothe reaction mass. The white colored solid appeared was then filteredand dried under vacuum (2.7 gm). mp 168-170° C.

IR (KBr): 3217, 3060, 2966, 2919, 2833, 1570, 1485, 1470, 1428, 1328,1256, 1054, 1026, 936, 887, 776, 759, 705 cm⁻¹. ¹H NMR (300 MHz, DMSO):δ 2.30 (s, 3H), 4.0 (s, 3H), 7.14 (d, 1H, J=7.8 Hz), 7.51 (t, 1H, J=7.8Hz), 7.86 (d, 1H, J=8.7 Hz), 8.03 (m, 2H), 8.53 (s, 1H), 11.28 (s, 1H).

Step 5: 1-methoxy-6-acetamido dibenzo[b,d]thiophene

Oxime (2.7 gm, 0.00992 mol) was dissolved in dry THF. Then thionylchloride (3.54 gm, 0.02977 mol) was added at 25° C. and the solution wasstirred for 30 minutes. Reaction mass was dumped in ice-water. Redcolored solid appeared was then filtered and washed with water. Thesolid was purified by silica gel (100-200) column chromatography using20% ethyl acetate in chloroform yield 1.5 gm, MP-decomposes at 170-174°C.

IR (KBr): 3296, 2938, 1658, 1568, 1471, 1428, 1260, 1096, 1025, 805, 775cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.10 (s, 3H), 3.46 (s, 3H), 7.12 (d, 1H,J=7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.76 (d, 1H,J=7.8 Hz), 7.94 (d, 1H, J=9 Hz), 8.56 (s, 1H), 10.22 (s, 1H).

Step 6: 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carbaldehyde

1-methoxy-6-acetamido dibenzo[b,d]thiophene (1.5 gm, 0.0055 mol) wassuspended in dichloromethane (25 ml) and the solution was cooled to −10°C. To this solution was added tin (IV) chloride (7.3 gm, 0.0275 mol) allat once at −10° C. under nitrogen atmosphere followed by drop wiseaddition of a solution of dichloromethyl methyl ether (0.948 gm, 0.008mol) in dichloromethane (5 ml) at −10° C. The reaction mixture wasallowed to attain room temperature under stirring for 30 min. Cold water(20 ml) was added to the reaction mixture and extracted withdichloromethane (25 ml×3). The organic layer was washed with water anddried over anhydrous sodium sulphate. The organic layer was concentratedunder vacuum to give the crude product brown sticky solid (800 mg), mp−247-250° C.

IR (KBr): 3347, 2923, 2851, 1678, 1664, 1578, 1557, 1530, 1459, 1278,1248, 1222, 1067, 1014, 822, 753, 693, 599 cm⁻¹. ¹H NMR (300 MHz, DMSO):δ 2.10 (s, 3H), 4.12 (s, 3H), 7.36 (d, 1H, J=8.10 Hz), 7.94 (d, 1H,J=9.0 Hz), 8.03 (d, 1H, J=8.7 Hz), 8.13 (d, 1H, J=8.4 Hz), 9.75 (s, 1H),10.23 (s, 1H), 10.49 (s, 1H).

Step 7: 1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carboxylic acid

To a solution of 1-methoxy-6-acetamidodibenzo[b,d]thiophene-4-carbaldehyde (800 mg, 0.00266 mol) in THF (15ml) and water (2 ml) was added sulfamic acid (387 mg, 0.004 mmol) whilestirring at 10° C. A solution of 80% sodium chlorite (360 mg, 0.004mmol) in water (2.0 mL) was added drop wise to the above reactionmixture over a period of 5 min

and was allowed to stir at 10° C. for additional 30 min. Water (150 ml)was added to obtain a precipitate which filtered and dried under vacuum(350 mg). MP-decomposes above 275° C.

IR (KBr): 3349, 3132, 3048, 2611, 1670, 1587, 1561, 1537, 1459, 1264,1013, 821, 782 cm⁻¹

Step 8: Mixed Anhydride Preparation

1-methoxy-6-acetamido dibenzo[b,d]thiophene-4-carboxylic acid (300 mg,0.000949 mol) was dissolved in DMF (10 ml) and the solution was cooledto −20° C. Isobutyl chloroformate (190 mg, 0.001423 mol) and diisopropyln-ethyl amine (244 mg, 0.0019 mol) was added at −20° c. and stirred for10-12 hrs. Reaction mass was dumped in water (100 ml). The solidappeared was filtered and dried under vacuum (270 mg). mp −125-130° C.

IR (KBr): 3283, 2960, 1779, 1743, 1658, 1561, 1527, 1459, 1370, 1293,1269, 1197, 1178, 1066, 1007, 813, 770, 730 cm⁻¹. ¹H NMR (300 MHz,DMSO): δ 0.95 (d, 6H, J=6.9 Hz), 2.08 (m, 4H), 4.13 (m, 5H), 7.27 (d,1H, J=8.1), 7.91 (d, 1H, J=8.7), 8.02 (d, 1H, J=9 Hz), 8.15 (d, 1H,J=8.4 Hz), 8.81 (s, 1H), 10.2 (s, 1H).

Step 9:N-(3,5-dichloropyrid-4-yl)-1-methoxy-6-acetamido-dibenzo[b,d]thiophene-4-carboxamide

To the stirred solution of anhydride (270 mg, 0.000655 mol) and 4-amino3,5-dichloro pyridine (118 mg, 0.00072 mol) in DMF (10 ml), 60% sodiumhydride (52 mg, 0.0013 mol) was added at −20° C. Reaction was maintainedfor 30 minutes. Reaction mass was dumped in water (100 ml). The solidappeared was acidified with 10% HCl and filtered. The residue was washedwith saturated sodium bicarbonate solution followed by water. The solidwas purified by silica gel (100-200) column chromatography using 20%acetone in chloroform. (Yield 12 mg) mp-decomposes above 275° C.

IR (KBr): 3430, 3349, 3293, 1657, 1563, 1527, 1458, 1260, 1025, 807, 775cm⁻¹. ¹H NMR (300 MHz, DMSO): δ 2.08 (s, 3H), 4.07 (s, 3H), 7.26 (d, 1H,J=8.4 Hz), 7.77 (d, 1H, J=8.1 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.99 (d, 1H,J=8.7 Hz), 8.19 (s, 1H), 8.37 (s, 1H).

EXAMPLE 60N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamidesodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide(Example 34) using ethanolic sodium ethoxide (1.0 eq.) in THF/ethanol.

¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (s, 3H), 7.30 (d, 1H, J=7.8 Hz), 7.42(t, 1H, J=73 Hz), 7.60 (d, 1H, J=9.0 Hz), 8.02-8.07 (m, 2H), 8.19 (s,2H), 8.98 (d, 1H, J=2.1 Hz), 10.25 (s, 1H).

EXAMPLE 61N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamidesodium salt

Was synthesized fromN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamide(Example 40) using ethanolic sodium ethoxide (1.0 eq.) in THF/ethanol

¹H NMR (300 MHz, DMSO-d₆) δ 6.68 (m, 1 Hz), 7.32 (d, 1H, J=8.7 Hz), 7.37(d, 1H, J=3.6 Hz), 7.44 (t, 1H, J=72 Hz), 7.68 (d, 1H, J=8.7 Hz),7.88-7.92 (m, 2H), 7.82 (d, 1H, J=8.7 Hz)), 8.18 (s, 2H), 9.20 (d, 1H,J=2.4 Hz), 10.33 (s, 1H).

In vitro Studies

Inhibition of Phosphodiesterase Enzymes (PDE4)

In this assay, PDE4 enzyme converts [³H] cAMP to the corresponding [³H]5′-AMP in proportion to the amount of PDE4 present. The [³H] 5′-AMP thenwas quantitatively converted to free [³H] adenosine and phosphate by theaction of snake venom 5′-nucleotidase. Hence, the amount of [³H]adenosine liberated is proportional to PDE4 activity.

The assay was performed with modification of the method of Thompson andAppleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau(Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both referencesincorporated herein by reference in their entirety, at 34° C. In a 200ul total reaction mixture, the reaction mixture contained 12.5 mM ofTris, 5 mM MgCl₂, 1 μM cAMP (cold) and ³H cAMP (0.1 uCi), (Amersham).Stock solutions of the compounds to be investigated were prepared inDMSO in concentrations such that the DMSO content in the test samplesdid not exceed 0.05% by volume to avoid affecting the PDE4 activity.Drug samples were then added in the reaction mixture (25 μt/tube). Theassay was initiated by addition of enzyme mix (75 μl) and the mixturewas incubated for 20 minutes at 34° C. The reaction was stopped byboiling the tubes for 2 mins at 100° C. in a water bath. After coolingon ice for 5 minutes and addition of 50 ug/reaction of 5′-nucleotidasesnake venom from Crotalus atrox incubation was carried out again for 20min. at 34° C. The unreacted substrate was separated from (³H) Adenosineby addition of Dowex AG 1-X8 (Biorad Lab), (400 ul) which wasprequilibrated (1:1:1) in water and ethanol. Reaction mixture was thenthoroughly mixed, placed on ice for 15 minutes, vortexed and centrifugedat 14,000 r.p.m. for 2 mins. After centrifugation, a sample of thesupernatant was taken and added in 24 well optiplates containingScintillant (1 ml) and mixed well. The samples in the plates were thendetermined for radioactivity in a Top Counter and the PDE4 activity wasestimated. PDE4 enzyme was present in quantities that yield <30% totalhydrolysis of substrate (linear assay conditions).

Additionally, activity of the compounds were tested against otherPhosphodiesterase enzymes, namely, PDE1(Ca.sup.2+/calmodulin-dependent), PDE 2(cGP-stimulated), PDE 3(cGP-inhibited), PDE 5 (cGP-specific) and PDE 6 (cGP-specific,photoreceptor).

Results were expressed as percent inhibition (IC₅₀) in nMconcentrations. The IC₅₀ values were determined from the concentrationcurves by nonlinear regression analysis.

Example No. IC₅₀ (nM) EC₅₀ (nM) 01 0.5058 8.57 02 1.027 2.07 03 0.76177.386 04 1.184 13.62 05 7.8 80.87 06 1.61 5.59 07 5.598 7.86 08 4.68110.3 09 1.035 137.8 10 1.853 38.18 11 0.887 4.34 12 0.557 16.18 1374.03 — 14 7.011 14.12 15 15.13 — 16 63.64 — 17 9.09 103.9 18 3.47 19.0819 4.792 9.008 20 10.26 8.29 21 1.19 23.8 22 1.283 9.34 23 3.776 4.13824 3.006 2.94 25 5.069 8.897 26 15.59 — 27 3.396 4.16 28 1.399 6.33 292.14 19.26 30 1.63 3.59 31 1.425 3.46 32 14.09 — 33 12.08 — 34 3.55214.76 35 8.199 146.2 36 4.637 8.44 37 21.53 >278.2 38 1.41 26.95 390.5981 9.19 40 22.04 11.33 41 156 — 42 959 — 43 17.93% at 1 uM — 441.719 3.93 45 0.7732 6.37 46 133.9 — 47 2.437 28.83 48 1.674 11.89 4913.2 — 50 9.93 146.9 51 1.98 121.8 52 8.13 821 53 1.05 71.45 54 236.9 —59 126.9 —

1. A method of treating asthma or chronic obstructive pulmonary diseasecomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of Formula (I)

wherein: R¹ is substituted or unsubstituted alkyl; R² is hydrogen; R³ ishydrogen; R⁴ is selected from the group consisting of

Ar is selected from the group consisting of substituted or unsubstitutedaryl and substituted or unsubstituted heteroaryl ring; X is selectedfrom the group consisting of O and S(O)_(q); Y is —C(O)NH; P is selectedfrom the group consisting of O and S; m is 0; n is 1; and q represents0, 1 or 2, or a N-oxide thereof, or a pharmaceutically acceptable saltthereof, wherein the substituents in the substituted groups may be thesame or different and in which one or more are selected from the groupconsisting of hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedamino, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclicring, substituted or unsubstiuted guanidine, —COOR^(x), —C(O)R^(x),—C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y), —NR^(x)CONR^(y)R^(z),—N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y), —(═N—N(R^(x))R^(y),—NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y)—NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, whereinR^(x), R^(y) and R² in each of the above groups can be hydrogen atom,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted heterocyclylalkyl ring, substituted orunsubstituted heteroarylalkyl, or substituted or unsubstitutedheterocyclic ring.
 2. The method according to claim 1, wherein Ar isoptionally substituted phenyl, optionally substituted pyrimidine,optionally substituted 4-pyridyl, optionally substituted 3-pyridyl,optionally substituted 2-pyridyl, optionally substituted4-pyridyl-N-oxide, optionally substituted 3-pyridyl-N-oxide oroptionally substituted 2-pyridyl-N-oxide in which optional substituents(one or more) may be same or different and are independently selectedfrom the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro,carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substitutedor unsubstituted alkylcarbonyloxy, substituted or unsubstituted aminoand mono or di substituted or unsubstituted alkylamino.
 3. The methodaccording to claim 1, wherein R¹ is unsubstituted alkyl.
 4. The methodaccording to claim 3, wherein R¹ is methyl.
 5. The method according toclaim 1, wherein R¹ is substituted alkyl.
 6. The method according toclaim 5, wherein R¹ is —CHF₂.
 7. The method according to claim 1,wherein P is O.
 8. The method according to claim 1, wherein X is chosenfrom the group consisting of O and S.
 9. The method according to claim8, wherein X═O.
 10. The method according to claim 1, wherein Ar isselected from the group consisting of substituted or unsubstituted4-pyridyl, substituted or unsubstituted 4-pyridyl-N-oxide, andsubstituted or unsubstituted 3-pyridyl.
 11. The method according toclaim 10, wherein Ar is selected from 4-pyridyl, 4-pyridyl-N-oxide and3-pyridyl in which the pyridyl group is substituted with one or morehalogen atoms.
 12. The method according to claim 11, wherein saidhalogen is chloro.
 13. The method according to claim 10, wherein Ar isselected from the group consisting of


14. The method according to claim 13, wherein Ar is


15. The method according to claim 1 wherein R⁴ is selected from thegroup consisting of


16. The method according to claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 17. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dimethylaminosulphonamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 18. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethanesulphonamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 19. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 20. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(3-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 21. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylcarboxamido-dibenzo[1,4]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 22. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-t-butylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 23. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 24. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 25. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamidesodium salt.
 26. The method according to claim 1, wherein the compoundisN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(fur-2-yl-carboxamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 27. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(cyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 28. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N,N-dicyclopropylcarbonylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 29. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoroacetamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 30. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethoxycarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 31. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isobutyloxycarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 32. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-phenoxycarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 33. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopropylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 34. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-trifluoromethylmethoxycarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 35. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-N,N-diethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 36. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-cyclopentylaminocarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 37. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 38. The method according to claim 1, whereinthe compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(N-methylpiperazin-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide hydrochloride.
 39. Themethod according to claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(4-hydroxypiperidin-1-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 40. The method according to claim 1, whereinthe compound is N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(morphol-4-ylcarboxamido)-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 41. The method according to claim 1, whereinthe compound is N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-isopropylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 42. The method according to claim 1, whereinthe compound is N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-n-hexylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 43. The method according to claim 1, whereinthe compound is N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-ethylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 44. The method according to claim 1, whereinthe compound is N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methylaminocarboxamido-dibenzo[b,d]furan-1-carboxamide or a pharmaceuticallyacceptable salt thereof.
 45. A method of treating asthma comprisingadministering to a subject in need thereof a therapeutically effectiveamount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 46. A method of treatingasthma comprising administering to a subject in need thereof atherapeutically effective amount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidesodium salt.
 47. The method according to claim 1, wherein the compoundisN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 48. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-N,N-dimethylaminosulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 49. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 50. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-(1-chloropropylcarboxamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 51. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-cyclopropylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 52. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-ethoxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 53. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 54. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-hydroxycarbonylcarboxamido-dibenzo[b,d]furan-1-carboxamidedi sodium salt.
 55. The method according to claim 1, wherein thecompound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 56. The method accordingto claim 1, wherein the compound isN1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide or apharmaceutically acceptable salt thereof.
 57. The method according toclaim 1, wherein the compound isN1-(4-methoxyphenyl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 58. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(ethylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 59. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(n-butylaminothiocarboxamido)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 60. The method accordingto claim 1, wherein the compound isN1-(pyrid-3-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide ora pharmaceutically acceptable salt thereof.
 61. The method according toclaim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide-N-oxideor a pharmaceutically acceptable salt thereof.
 62. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamide-N-oxideor a pharmaceutically acceptable salt thereof.
 63. The method accordingto claim 1, wherein the compound isN-(pyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide ora pharmaceutically acceptable salt thereof.
 64. The method according toclaim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 65. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylaminocarbonylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 66. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 67. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-hydroxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 68. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidedisodium salt.
 69. The method according to claim 1, wherein the compoundisN-(3,5-dichloropyrid-4-yl)-1-methoxy-6-acetamido-dibenzo[b,d]thiophene-4-carboxamideor a pharmaceutically acceptable salt thereof.
 70. The method accordingto claim 1, wherein the compound isN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamidesodium salt.
 71. The method according to claim 1, wherein the compoundisN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-fur-2-ylcarboxamido-dibenzo[b,d]furan-1-carboxamidesodium salt.
 72. The method according to claim 1, wherein the compoundis N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[d,b]furan-1-carboxamide-N-oxide or apharmaceutically acceptable salt thereof.
 73. A method of treatingchronic obstructive pulmonary disease comprising administering to asubject in need thereof a therapeutically effective amount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof.
 74. A method of treatingchronic obstructive pulmonary disease comprising administering to asubject in need thereof a therapeutically effective amount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidesodium salt.
 75. A method of treating asthma comprising administering toa subject in need thereof a therapeutically effective amount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidemonosodium salt.
 76. A method of treating chronic obstructive pulmonarydisease comprising administering to a subject in need thereof atherapeutically effective amount ofN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidemonosodium salt.
 77. A method of treating chronic obstructive pulmonarydisease comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 78. A method of treating chronic obstructivepulmonary disease comprising administering to a subject in need thereofa therapeutically effective amount of a pharmaceutical compositioncomprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidesodium salt and a pharmaceutically acceptable excipient.
 79. A method oftreating chronic obstructive pulmonary disease comprising administeringto a subject in need thereof a therapeutically effective amount of apharmaceutical composition comprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidemonosodium salt and a pharmaceutically acceptable excipient.
 80. Amethod of treating asthma comprising administering to a subject in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamideor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.
 81. A method of treating asthma comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidesodium salt and a pharmaceutically acceptable excipient.
 82. A method oftreating asthma comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprisingN-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-methanesulfonamido-dibenzo[b,d]furan-1-carboxamidemonosodium salt and a pharmaceutically acceptable excipient.
 83. Themethod according to claim 45, wherein the subject is a human.
 84. Themethod according to claim 75, wherein the subject is a human.
 85. Themethod according to claim 73, wherein the subject is a human.
 86. Themethod according to claim 76, wherein the subject is a human.
 87. Themethod of claim 1, wherein the subject is suffering from asthma.
 88. Themethod of claim 1, wherein the subject is suffering from chronicobstructive pulmonary disease.